Acylguanidines for treating osteoarthritis

ABSTRACT

The present invention relates to compounds of the formula (I) and in particular to medicaments comprising at least one compound of the formula I for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions in the triggering of which cathepsin D is involved, in particular for use in the treatment and/or prophylaxis of osteoarthritis, traumatic cartilage injuries, arthritis, pain, allodynia or hyperalgesia.

The present invention relates to compounds of the formula I and in particular medicaments comprising at least one compound of the formula I for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states in the triggering of which cathepsin D is involved, in particular for use in the treatment and/or prophylaxis of arthrosis, traumatic cartilage injuries, arthritis, pain, allodynia or hyperalgesia.

BACKGROUND OF THE INVENTION

Arthrosis is the most widespread joint disease worldwide, and radiological signs of arthrosis are found in the majority of over-65 year olds. In spite of this significant importance for the health system, the causes of arthrosis remain unclear to date, and effective preventative measures furthermore remain a distant aim. A reduction in the joint gap (caused by destruction of the joint cartilage), together with changes in the subchondral bone and osteophyte formation, are the radiological characteristics of the disease. For the patient, however, pain (load-dependent and nocturnal rest pain) with subsequent function impairments are to the fore. It is also these which force the patient into social isolation with corresponding secondary diseases.

The term arthrosis according to an unofficial definition in Germany denotes “joint wear” which exceeds the usual extent for the age. The causes are regarded as being excessive load (for example increased body weight), connatal or traumatic causes, such as malpositioning of the joints or also bone deformations due to bone diseases, such as osteoporosis. Arthrosis can likewise arise as a consequence of another disease, for example joint inflammation (arthritis) (secondary arthrosis), or accompany overload-induced effusion (secondary inflammation reaction) (activated arthrosis). The Anglo-American specialist literature differentiates between osteoarthrosis (osteoarthritis [OA]), in which the destruction of the joint surfaces can probably be attributed principally to the effects of load, and arthritis (rheumatoid arthritis [RA]), in which joint degeneration due to an inflammatory component is to the fore.

In principle, arthrosis is also differentiated according to its cause. Arthrosis alcaptonurica is based on increased deposition of homogenitic acid in joints in the case of previously existing alcaptonuria. In the case of haemophilic arthrosis, regular intra-articular bleeding occurs in the case of haemophilia (haemophilic joint). Arthrosis urica is caused by the mechanical influence of urate crystals (uric acid) on the healthy cartilage (W. Pschyrembel et al.: Klinisches Worterbuch mit klinischen Syndromen and einem Anhang Nomina Anatomica [Clinical Dictionary with Clinical Syndromes and a Nomina Anatomica Annex]. Verlag Walter de Gruyter & Co, 253rd Edition, 1977).

The classical cause of arthrosis is dysplasia of joints. Using the example of the hip, it becomes clear that the zone with the greatest mechanical stress in the case of a physiological hip position represents a significantly larger area than in the case of a dysplastic hip. However, the stresses caused by the forces acting on the joint are substantially independent of the joint shape. They are essentially distributed over the main stress zone(s). A greater pressure will thus arise in the case of a relatively small zone than in the case of a larger one. The biomechanical pressure on the joint cartilage is thus greater in the case of a dysplastic hip than in the case of a physiological hip position. This rule is generally regarded as the cause of the increased occurrence of arthrotic changes in supporting joints which differ from the ideal anatomical shape.

If the consequences of an injury are responsible for premature wear, the term post-traumatic arthrosis is used. Further causes of secondary arthrosis that are being discussed are mechanical, inflammatory, metabolic, chemical (quinolones), trophic, hormonal, neurological and genetic reasons. In most cases, however, the diagnosis given is idiopathic arthrosis, by which the doctor means an apparent absence of a causal disease (H. I. Roach and S. Tilley, Bone and Osteoarthritis F. Bronner and M. C. Farach-Carson (Editors), Verlag Springer, Volume 4, 2007).

Medicinal causes of arthrosis can be, for example, antibiotics of the gyrase inhibitor type (fluoroquinolones, such as ciprofloxacin, levofloxacin). These medicaments result in complexing of magnesium ions in poorly vascularised tissues (hyaline joint cartilage, tendon tissue), which has the consequence that irreversible damage occurs to connective tissue. This damage is generally more pronounced in the growth phase in children and juveniles. Tendinopathies and arthropathies are known side effects of this class of medicaments. In adults, these antibiotics result in accelerated physiological degradation of the hyaline joint cartilage according to information from independent pharmacologists and rheumatologists (M. Menschik et al., Antimicrob. Agents Chemother. 41, 1997, pp. 2562-2565; M. Egerbacher et al., Arch. Toxicol. 73, 2000, pp. 557-563; H. Chang et al., Scand. J. Infect. Dis. 28, 1996, pp. 641-643; A. Chaslerie et al., Therapie 47, 1992, p. 80). Extended treatment with phenprocoumone can also favour arthrosis by decreasing bone density in the case of stresses of the joint internal structure.

Besides age, known risk factors for osteoarthrosis are mechanical overload, (micro)traumas, joint destabilisation caused by loss of the securing mechanisms, and genetic factors. However, neither the occurrence nor possible interventions have been fully explained (H. I. Roach and S. Tilley, Bone and Osteoarthritis F. Bronner and M. C. Farach-Carson (Editors), Verlag Springer, Volume 4, 2007).

In a joint affected by arthrosis, the content of nitrogen monoxide is increased in some cases. A similar situation has been observed due to high mechanical irritation of cartilage tissue (P. Das et al., Journal of Orthopaedic Research 15, 1997, pp. 87-93. A. J. Farrell et al. Annals of the Rheumatic Diseases 51, 1992, pp. 1219-1222; B. Fermor et al., Journal of Orthopaedic Research 19, 2001, pp. 729-737), whereas moderate mechanical stimulation tends to have a positive effect. The action of mechanical forces is thus causally involved in the progress of osteoarthrosis (X. Liu et al., Biorheology 43, 2006, pp. 183-190).

In principle, arthrosis therapy follows two aims: firstly freedom from pain under normal load and secondly the prevention of mechanical restrictions or changes in a joint. These aims cannot be achieved in the long term by pain treatment as a purely symptomatic therapy approach, since this cannot halt the progress of the disease. If the latter is to be achieved, the cartilage destruction must be stopped. Since the joint cartilage in adult patients cannot regenerate, the elimination of pathogenetic factors, such as joint dysplasia or malpositions, which result in increased point pressure on the joint cartilage, is in addition enormously important.

Finally, it is attempted to prevent or stop the degeneration processes in the cartilage tissue with the aid of medicaments.

An essential factor for the functioning state of the joint cartilage and thus the resistance thereof to stress is the extracellular matrix, which primarily consists of collagens, proteoglycans and water. The enzymes involved in degradation of the extracellular matrix include, in particular, the metalloproteases, aggrecanases and cathepsin enzymes. However, further enzymes can in principle also degrade cartilage matrix, for example plasmin, kallikrein, neutrophilelastase, tryptase and chymase.

Cathepsins belong to the papain superfamily of lysosomal proteases. Cathepsins are involved in normal proteolysis and the conversion of target proteins and tissues and in the initiation of proteolytic cascades and proenzyme activations. In addition, they are involved in MHC class II expression (Baldwin (1993) Proc. Natl. Acad. Sci., 90: 6796-6800; Mixuochi (1994) Immunol. Lett., 43: 189-193). However, abnormal cathepsin expression can result in severe diseases. Thus, increased cathepsin expression has been detected in cancer cells, for example in breast, lung, prostate, glioblastoma and head and neck cancer, and it has been shown that cathepsins are associated with inadequate therapy success in breast, lung, head and neck cancer, and in brain tumours (Kos et al. (1998) Oncol. Rep., 5: 1349-1361; Yan et al. (1998) Biol. Chem., 379:113-123; Mort et al.; (1997) Int. J. Biochem. Cell Biol., 29: 715-720; Friedrick et al. (1999) Eur. J Cancer, 35: 138-144). In addition, abnormal cathepsin expression is apparently involved in the development of inflammatory and non-inflammatory diseases, such as, for example, rheumatoid arthritis and osteoarthrosis (Keyszer (1995) Arthritis Rheum., 38: 976-984).

The molecular mechanism of cathepsin activity has not been fully explained. On the one hand, it has been found that, for example, induced cathepsin expression protects B cells from which serum is taken against apoptosis, and that treatment of the cells with antisense oligonucleotides of cathepsin B induces apoptosis (Shibata et al. (1998) Biochem. Biophys. Res. Commun., 251: 199-20; Isahara et at. (1999) Neuroscience, 91: 233-249). These reports suggest an anti-apoptotic role of cathepsins. However, they are in complete contrast to earlier reports, which describe cathepsins as apoptosis mediators (Roberts et al (1997) Gastroenterology, 113: 1714-1726; Jones et al. (1998) Am. J. Physiol., 275: G723-730).

Cathepsins are synthesised as inactive zymogens on ribosomes and transferred into the lysosomal system. After proteolytic cleaving-off of the N-terminal propeptide, the cathepsin concentration in the acidic environment of the lysosomes increases to 1 mM, and the cathepsins are released into the extracellular medium by the lysosomes.

In the case of cathepsins, a differentiation is made between the cysteine cathepsins B, C, H, F, K, L, O, S, V and W, the aspartyl cathepsins D and E, and the serine cathepsin G.

Examples of cathepsin inhibitors in clinical development are cathepsin K inhibitors for the treatment of arthrosis and cathepsin S inhibitors for the treatment of arthritis, neuropathic pain and psoriasis.

Besides cathepsin D, the aspartyl proteases also include the HIV aspartyl protease (HIV-1 protease), renin, pepsin A and C, BACE (Asp2, memapsin), plasmepsins and the aspartyl haemoglobinases (Takahashi, T. et al., Ed. Aspartic Proteinases Structure, Function, Biology and Biomedical Implications (Plenum Press, New York, 1995), Adams, J. et al., Ann. Rep. Med. Chem. 31, 279-288, 1996; Edmunds J. et al., Ann. Rep. Med. Chem. 31, 51-60, 1996; Miller, D. K. et al., Ann. Rep. Med. Chem 31, 249-268, 1996). Cathepsin D is normally involved in the degradation of intracellular or phagocytised proteins and thus plays an important role in protein metabolism (Helseth, et al., Proc. Natl. Acad. Sci. USA 81, 3302-3306, 1984), in protein catabolism (Kay, et al., Intracellular Protein Catabolism (eds. Katunuma, et al., 155-162, 1989) and in antigen processing (Guagliardi, et al., Nature, 343, 133-139, 1990; Van Noort, et al., J. Biol. Chem., 264, 14159-14164, 1989).

Increased cathepsin D levels are associated with a number of diseases. Thus, increased cathepsin D levels correlate with a poor prognosis in breast cancer and with increased cell invasion and an increased risk of metastases, and shorter relapse-free survival time after therapy and a lower survival rate overall (Westley B. R. et al., Eur. J. Cancer 32, 15-24, 1996; Rochefort, H., Semin. Cancer Biol. 1:153, 1990; Tandon, A. K. et al., N. Engl. J. Med. 322, 297, 1990). The cathepsin D secretion rate in breast cancer is promoted by overexpression of the gene and by modified processing of the protein. Increased levels of cathepsin D and other proteases, such as, for example, collagenase, produced in the immediate vicinity of a growing tumour, could degrade the extracellular matrix in the environment of the tumour and thus promote the detachment of tumour cells and invasion into new tissue via the lymph and circulation system (Liotta L. A., Scientific American February: 54, 1992; Liotta L. A. and Stetler-Stevenson W. G., Cancer Biol. 1:99, 1990; Liaudet E., Cell Growth Differ. 6:1045-1052, 1995; Ross J. S., Am. J. Clin. Pathol. 104:36-41, 1995; Dickinson A. J., J. Urol. 154:237-241, 1995).

Cathepsin D is in addition associated with degenerative changes in the brain, such as, for example, Alzheimer's disease. Thus, catepsin D is associated with cleavage of the amyloid-β precursor protein or of a mutant precursor which increases the expression of the amyloid protein in transfected cells (Cataldo, A. M. et al., Proc. Natl. Acad. Sci. 87: 3861, 1990; Ladror, U. S. et al., J. Biol. Chem. 269: 18422, 1994, Evin G., Biochemistry 34: 14185-14192, 1995). The amyloid-β protein, which is formed by proteolysis of the amyloid-β precursor protein, results in the formation of plaques in the brain and appears to be responsible for the development of Alzheimer's disease. Increased cathepsin D levels have also been found in the cerebrospinal fluid of Alzheimer's patients, and a high proteolytic activity of cathepsin D compared with the mutant amyloid-β precursor protein has been found (Schwager, A. L., et al. J. Neurochem. 64:443, 1995). In addition, a significant increase in cathepsin D activity is measured in biopsies from Huntington's disease patients (Mantle D., J. Neurol. Sci. 131: 65-70, 1995).

Cathepsin D is thought to play an essential role at various levels in the development of arthrosis. Thus, increased mRNA levels of cathepsin D are measured in the joint cartilage of the hip joint head in dogs with spontaneous arthrosis compared with healthy dogs (Clements D. N. et al., Arthritis Res. Ther. 2006; 8(6): R158; Ritchlin C. et al., Scand. J. Immunnol. 40: 292-298, 1994). Devauchelle V. et al. (Genes Immun. 2004, 5(8): 597-608) also show different expression rates of cathepsin D in human patients in the case of arthrosis compared with rheumatoid arthritis (see also Keyszer G. M., Arthritis Rheum. 38: 976-984, 1995). Cathepsin D also appears to play a role in mucolipidosis (Kopitz J., Biochem. J. 295, 2: 577-580, 1993).

The lysosomal endopeptidase cathepsin D is the most widespread pro-teinase in the chondrocytes (Ruiz-Romero C. et al., Proteomics. 2005, 5(12): 3048-59). In addition, the proteolytic activity of cathepsin D has been detected in the cultivated synovium from osteoarthrosis patients (Bo G. P. et al., Clin. Rheumatol. 2009, 28(2): 191-9), and increased proteolytic activity is also found in synovectomy tissue of patients with rheumatoid arthritis (Taubert H. et al., Autoimmunity. 2002, 35(3): 221-4). Lorenz et al. (Proteomics. 2003, 3(6): 991-1002) thus also write that, although the lysosomal and secreted aspartyl protease cathepsin D has not yet been studied in detail with respect to arthritis and arthrosis, in contrast to cathepsins B and L, Lorenz et al. found, however, higher protein levels of cathepsin D in the synovial tissue of patients with arthrosis compared with patients with rheumatoid arthritis.

Gedikoglu et al. (Ann. Rheum. Dis. 1986, 45(4): 289-92) have likewise detected an increased proteolytic activity of cathepsin D in synovial tissue and Byliss and Ali (Biochem. J. 1978, 171(1): 149-54) in the cartilage of patients with arthrosis.

In the case of arthrosis, a reduction in the pH occurs in regions of the cartilage. This reduction in the pH is of crucial importance for the under-standing of catabolic processes in the cartilage.

In the case of arthrosis, a direct correlation is thus also found between a low pH in the joint tissue and the severity and progress of the disease. At a pH of 5.5, autodigestion of the cartilage occurs. This can be inhibited virtually completely by pepstatin or ritonavir in explant cultures (for example from mouse, cow or human). This suggests an essential role, or even a key role, of cathepsin D in arthrosis, since pepstatin inhibits aspartyl proteases with one exception—BACE 1—and only these two aspartyl proteases have hitherto been identified in the cartilage tissue. Thus, Bo G. P. et al. (Clin. Rheumatol. 2009, 28(2): 191-9) also describe the important role of cathepsin D in pathological changes in joints.

The best-known aspartyl protease inhibitor is pepstatin, a peptide which was originally isolated from a Streptomyces culture. Pepstatin is effective against pepsin, cathepsin and renin. Many aspartyl protease inhibitors have therefore been modelled on the example of the structure of pepstatin (U.S. Pat. No. 4,746,648; Umezawa, H, et al., J Antibiot (Tokyo) 23: 259-62, 1970; Morishima, H., et al., J. Antibiot. (Tokyo) 23: 263-5, 1970; Lin, Ty and Williams, H R., J. Biol. Chem. 254: 11875-83, 1979; Jupp, R A, et al., Biochem. J. 265: 871-8, 1990; Agarwal, N S and Rich, D H, J. Med. Chem. 29: 2519-24, 1986; Baldwin, E T, et al., Proc. Natl. Acad. Sci., USA 90: 6796-800, 1993; Francis, S E et al., EMBO J 13: 306-17, 1994).

Aspartyl proteases and cathepsin D are frequently described as target proteins for active compounds for the treatment of neurodegenerative diseases, cognitive disorders, dementia, Alzheimer's, cancer, malaria, HIV infection and diseases of the cardiovascular system, and inhibitors of aspartyl proteases or cathepsin D are disclosed for the treatment of these diseases, such as, for example, in WO 2009013293, EP 1987834, EP 1872780, EP 1867329, EP 1745778, EP 1745777, EP 1745776, WO 1999002153, WO 1999055687, U.S. Pat. No. 6,150,416, WO 2003106405, WO 2005087751, WO 2005087215, WO 2005016876, US 2006281729, WO 2008119772, WO 2006074950, WO 2007077004, WO 2005049585, U.S. Pat. No. 6,251,928 and U.S. Pat. No. 6,150,416.

Peptide derivatives or guanidines as analgesics are known, for example, from WO 9524421. Further acylguanidines for the treatment of cancer and/or for treatment of neurodegenerative are known from WO 2010025448, WO 2011010013, WO 9920599 and WO 9736862, acylguanidines for the treatment of coagulation disorders are known from WO 9612499. Acylguanidines for the treatment of migraine are known from EP 1728784. Diazaheterocyclic guandines are known from U.S. Pat. No. 3,098,066.

WO 02236554 discloses acylguandines as 5-HT₇ receptor antagonists for the treatment of depression, schizophrenia and sleep disorders.

Although the known cathepsin D inhibitors and the two model compounds pepstatin and ritonavir effectively inhibit cathepsin D activity, they have, however, quite low selectivity for other aspartyl proteases. The role of the renin-angiotensin system (RAS) in the regulation of blood pressure and the fluid and electrolyte balance (Oparil, S. et al., N. Engl. J. Med. 1974; 291: 381-401/446-57) and the efficacy of renin and pepsin inhibitors in diseases of the cardiovascular system is adequately known, and thus numerous side effects can be expected, in particular on oral or systemic administration of these low-selectivity cathepsin D inhibitors, and systemic complications can also be expected on local application due to diffusion of the compounds. In addition, the peptidic compounds in particular have low stability and are therefore not suitable for oral or systemic administration.

The invention was based on the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

The object of the present invention was, in particular, to find novel active compounds and particularly preferably novel cathepsin D inhibitors which can be employed for the prevention and treatment of arthrosis and have, in particular, high selectivity for cathepsin D compared with renin and pepsin. In addition, the aim was to find novel cathepsin D inhibitors which are sufficiently stable, at least on local or intra-articular administration.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that the acylguanidines according to the invention inhibit cathepsin D highly effectively and at the same time have high selectivity for cathepsin D compared with renin and pepsin, and thus few side effects can be expected on use thereof for the treatment of arthrosis. In addition, the compounds according to the invention have adequately good stability in synovial fluid, meaning that they are suitable for intra-articular administration and thus for the treatment of arthrosis. It has likewise surprisingly been found that the acylguanidines according to the invention are able to reduce inflammation-induced thermal hyperalgesia depending on the dose.

The invention relates to acylguanidines of the general formula I,

in which

-   R¹, R², R³ are selected, independently of one another, from the     group consisting of H, a straight-chain or branched alkyl, alkenyl     or alkynyl group having 1-10 C atoms which is unsubstituted or     mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-, bi- or     tricyclic cycloalkyl group having 3-20 C atoms which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic cycloalkylalkyl group having 4-20 C atoms which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic cycloalkylalkenyl group having 5-20 C atoms which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic cycloalkylalkynyl group having 5-20 C atoms which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic cycloalkenyl group having 5-20 C atoms which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic cycloalkenylalkyl group having 5-20 C atoms which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic heterocycloalkyl group having 1-14 C atoms and 1-7     heteroatoms selected, independently of one another, from N, O and S     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵,     R⁶, a mono- or bicyclic heterocycloalkylalkyl group having 2-20 C     atoms and 1-7 heteroatoms selected, independently of one another,     from N, O and S which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic aryl group having     3-20 C atoms which is unsubstituted or mono-, di- or trisubstituted     by R⁴, R⁵, R⁶, a mono- or bicyclic arylalkyl group having 4-20 C     atoms which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶, a mono- or bicyclic arylalkenyl group having 5-20 C atoms     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵,     R⁶, a mono- or bicyclic arylalkynyl group having 5-20 C atoms which     is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a     mono- or bicyclic heteroaryl group having 1-14 C atoms and having     1-7 heteroatoms selected, independently of one another, from N, O     and S which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶, a mono- or bicyclic heteroarylalkyl group having 2-20 C     atoms and having 1-7 heteroatoms selected, independently of one     another, from N, O and S which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic heteroarylalkenyl     group having 3-20 C atoms and having 1-7 heteroatoms selected,     independently of one another, from N, O and S which is unsubstituted     or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, and a     heteroarylalkynyl group having 3-20 C atoms and having 1-7     heteroatoms selected, independently of one another, from N, O and S     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵,     R⁶, where, in each case independently of one another, the CH₂—,     CH═CH— or —C≡C— groups of the alkyl, alkenyl and alkynyl groups may     be replaced by O, N, S, SO, SO₂, NH, NCH₃, —OCO—, —NHCONH—, —NHCO—,     —NRSO₂A—, —COO—, —CONN—, —NCH₃CO— or —CONCH₃— and/or 1-20H atoms may     be replaced by F and/or Cl, -   R⁴, R⁵, R⁶ are selected, independently of one another, from the     group consisting of H, A, ═O, ═S, EN, (CH₂)_(n)Hal,     (CH₂)_(n)CH(Hal)₂, (CH₂)_(n)C(Hal)₃, (CH₂)_(n)OC(Hal)₃,     (CH₂)_(n)N(C[Hal]₃)₂, (CH₂)_(n)OC(Hal)₃, (CH₂)_(n)NO₂, (CH₂)_(n)CN,     (CH₂)_(n)NR⁷R⁸, (CH₂)_(n)O(CH₂)_(m)NR⁷R⁸, (CH₂)_(n)NR⁷(CH₂)_(n),     NR⁷R⁸, (CH₂)_(n)O(CH₂)_(m)OR⁷, (CH₂)_(n)NR⁷(CH₂)_(m)OR⁸,     (CH₂)_(n)COOR⁷, (CH₂)_(n)CH═O, (CH₂)_(n)OR⁷,     (CH₂)_(n)CHOH(CH₂)_(n)OR⁷, (CH₂)_(n)COR⁷, (CH₂)_(n)OOCR⁷,     (CH₂)_(n)CONR⁷R⁸, C(O)NHA, C(O)NHANH₂ (CH₂)_(n)NR⁷COR⁸,     (CH₂)_(n)NR⁷CONR⁷R⁸, (CH₂)_(n)NR⁷SO₂R⁷, (CH₂)_(n)SO₂NR⁷R⁸,     (CH₂)_(n)SO₂R⁷R⁸, (CH₂)_(n)S(O)_(m)R⁷, (CH₂)_(n)OC(O)R⁷,     (CH₂)_(n)COR⁷, (CH₂)_(n)CH═S, (CH₂)_(n)SR⁷, CH═N-OA, CH₂CH═N-OA,     (CH₂)_(n)NHOA, (CH₂)_(n)CH═N—R⁷, (CH₂)_(n)OC(O)NR⁷R⁷,     (CH₂)_(n)NR⁷COOR⁸, (CH₂)_(n)N(R⁷)CH₂CH₂OR⁹,     (CH₂)_(n)N(R⁷)CH₂CH₂OCF₃, (CH₂)_(n)N(R⁷)C(R⁹)HCOOR⁸,     (CH₂)_(n)N(R⁷)C(R⁹)HCOR⁸, (CH₂)_(n)N(R⁷)CH₂CH₂N(R⁸)CH₂COOR⁷,     (CH₂)_(n)N(R⁷)CH₂CH₂NR⁷R⁸, CH═CHCOOR⁹, CH═CHCH₂NR⁷R⁸, CH═CHCH₂NR⁷R⁸,     CH═CHCH₂OR⁹, (CH₂)_(n)N(COOR⁹)COOR¹⁰, (CH₂)_(n)N(CONH₂)COOR⁹,     (CH₂)_(n)N(CONH₂)CONH₂, (CH₂)_(n)N(CH₂COOR⁹)COOR¹⁰,     (CH₂)_(n)N(CH₂CONH₂)COOR⁹, (CH₂)_(n)N(CH₂CONH₂)CONH₂,     (CH₂)_(n)CHR⁹COR¹⁰, (CH₂)_(n)CHR⁹COOR¹⁰, (CH₂)_(n)CHR⁹CH₂OR¹⁰,     (CH₂)_(n)OCN and (CH₂)_(n)NCO, -   R⁷, R⁸ are, independently of one another, H or A and, in NR⁷R⁸, R⁷     and R⁸, together with the N atom to which they are bonded, may form     a 5-, 6- or 7-membered heterocycle, which may optionally contain one     or two further heteroatoms selected from the group consisting of N,     O and S, -   R⁹, R¹⁰ are selected, independently of one another, from the group     consisting of H, Hal and A, -   A is selected from the group consisting of alkyl, alkenyl, alkynyl     and cycloalkyl, -   n, m are, independently of one another, 0, 1, 2, 3, 4, or 5, and -   Hal is, independently of one another, F, Cl, Br or I,     and physiologically acceptable salts, derivatives, solvates,     prodrugs and stereoisomers thereof, including mixtures thereof in     all ratios.

The invention preferably relates to all above-mentioned compounds of the formula I in which

-   R¹ is selected from the group consisting of: a straight-chain or     branched alkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono-, bi- or tricyclic cycloalkyl     group which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶, a mono- or bicyclic cycloalkylalkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic aryl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic arylalkyl group     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵,     R⁶, a mono- or bicyclic heteroaryl group which is unsubstituted or     mono-, di- or trisubstituted by R⁴, R⁵, R⁶ and a mono- or bicyclic     heteroarylalkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶     and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, n, m and Hal have the     meanings indicated above, and physiologically acceptable salts,     derivatives, solvates, prodrugs and stereoisomers thereof, including     mixtures thereof in all ratios.

The invention furthermore preferably relates to all above-mentioned compounds of the formula I in which

-   R² is selected from the group consisting of: H, a straight-chain or     branched alkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono-, bi- or tricyclic cycloalkyl     group which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶, a mono- or bicyclic cycloalkylalkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic aryl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶ and a mono- or bicyclic arylalkyl group     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶     and R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, n, m and Hal have the     meanings indicated above, and physiologically acceptable salts,     derivatives, solvates, prodrugs and stereoisomers thereof, including     mixtures thereof in all ratios.

The invention furthermore preferably relates to all above-mentioned compounds of the formula I in which

-   R² denotes H or a straight-chain or branched alkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a     monocyclic cycloalkylalkyl group which is unsubstituted or mono-,     di- or trisubstituted by R⁴, R⁵, R⁶ or a monocyclic arylalkyl group     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶     and R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, n, m and Hal have the     meanings indicated above, and physiologically acceptable salts,     derivatives, solvates, prodrugs and stereoisomers thereof, including     mixtures thereof in all ratios.

The invention furthermore preferably relates to all above-mentioned compounds of the formula I in which

-   R² denotes H or a straight-chain or branched alkyl,     cyclohexylmethyl, cyclohexylethyl, benzyl or phenylethyl, each of     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵,     R⁶,     and R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, n, m and Hal have the     meanings indicated above, and physiologically acceptable salts,     derivatives, solvates, prodrugs and stereoisomers thereof, including     mixtures thereof in all ratios.

The invention furthermore preferably relates to all above-mentioned compounds of the formula I in which

-   R² denotes H or a straight-chain or branched alkyl,     cyclohexylmethyl, cyclohexylethyl, benzyl or phenylethyl, each of     which is unsubstituted or mono-, di- or trisubstituted by     (CH₂)_(n)OR⁷ or Hal,     and R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, n, m and Hal have the     meanings indicated above, and physiologically acceptable salts,     derivatives, solvates, prodrugs and stereoisomers thereof, including     mixtures thereof in all ratios.

The invention furthermore preferably relates to all above-mentioned compounds of the formula I in which

-   R² denotes H or a straight-chain or branched alkyl,     cyclohexylmethyl, cyclohexylethyl, benzyl or phenylethyl, which is     unsubstituted or mono-, di- or trisubstituted by (CH₂)_(n)OR⁷ or Cl,     and R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, n, m and Hal have the     meanings indicated above, and physiologically acceptable salts,     derivatives, solvates, prodrugs and stereoisomers thereof, including     mixtures thereof in all ratios.

The invention furthermore preferably relates to all above-mentioned compounds of the formula I in which

-   R³ is selected from the group consisting of: a straight-chain or     branched alkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono-, bi- or tricyclic cycloalkyl     group which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶, a mono- or bicyclic cycloalkylalkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic heterocycloalkyl group which is unsubstituted or mono-,     di- or trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic     heterocycloalkylalkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic aryl group which     is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a     mono- or bicyclic arylalkyl group which is unsubstituted or mono-,     di- or trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic heteroaryl     group which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶ and a mono- or bicyclic heteroarylalkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶     and R¹, R², R⁴, R⁵, R⁶, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, n, m and Hal have     the meanings indicated above, and physiologically acceptable salts,     derivatives, solvates, prodrugs and stereoisomers thereof, including     mixtures thereof in all ratios.

The invention particularly preferably relates to all above-mentioned compounds of the formula I in which

-   R¹ is selected from the group consisting of: a straight-chain or     branched alkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono-, bi- or tricyclic cycloalkyl     group which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶, a mono- or bicyclic cycloalkylalkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic aryl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic arylalkyl group     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵,     R⁶, a mono- or bicyclic heteroaryl group which is unsubstituted or     mono-, di- or trisubstituted by R⁴, R⁵, R⁶ and a mono- or bicyclic     heteroarylalkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, -   R² is selected from the group consisting of: H, a straight-chain or     branched alkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono-, bi- or tricyclic cycloalkyl     group which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶, a mono- or bicyclic cycloalkylalkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic aryl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶ and a mono- or bicyclic arylalkyl group     which is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵,     R⁶, -   R³ is selected from the group consisting of: a straight-chain or     branched alkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono-, bi- or tricyclic cycloalkyl     group which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶, a mono- or bicyclic cycloalkylalkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a mono-     or bicyclic heterocycloalkyl group which is unsubstituted or mono-,     di- or trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic     heterocycloalkylalkyl group which is unsubstituted or mono-, di- or     trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic aryl group which     is unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶, a     mono- or bicyclic arylalkyl group which is unsubstituted or mono-,     di- or trisubstituted by R⁴, R⁵, R⁶, a mono- or bicyclic heteroaryl     group which is unsubstituted or mono-, di- or trisubstituted by R⁴,     R⁵, R⁶ and a mono- or bicyclic heteroarylalkyl group which is     unsubstituted or mono-, di- or trisubstituted by R⁴, R⁵, R⁶,     and R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, n, m and Hal have the meanings     indicated above, and physiologically acceptable salts, derivatives,     solvates, prodrugs and stereoisomers thereof, including mixtures     thereof in all ratios.

The invention very particularly preferably relates to all above-mentioned compounds of the formula I in which

-   R¹ denotes a straight-chain or branched alkyl group, mono-, bi- or     tricyclic cycloalkyl group, mono- or bicyclic cycloalkylalkyl group,     mono- or bicyclic aryl group, mono- or bicyclic arylalkyl group,     mono- or bicyclic heteroaryl group or mono- or bicyclic     heteroarylalkyl group which is unsubstituted or mono-, di- or     trisubstituted by (CH₂)_(n)OR⁷, EN, Hal, OCF₃, CF₃, ═O, A,     (CH₂)_(n)CN, (CH₂)_(n)NR⁷SO₂R⁷ or (CH₂)_(n)SO₂NR⁷R⁸, -   R² denotes H or a straight-chain or branched alkyl, monocyclic     cycloalkylalkyl or monocyclic arylalkyl, each of which is     unsubstituted or mono-, di- or trisubstituted by (CH₂)_(n)OR⁷ or     Hal, -   R³ denotes a straight-chain or branched alkyl group, mono-, bi- or     tricyclic cycloalkyl group, mono- or bicyclic cycloalkylalkyl group,     mono- or bicyclic heterocycloalkyl group, mono- or bicyclic     heterocycloalkylalkyl group, mono- or bicyclic aryl group, mono- or     bicyclic arylalkyl group, mono- or bicyclic heteroaryl group or     mono- or bicyclic heteroarylalkyl group which is unsubstituted or     mono-, di- or trisubstituted by (CH₂)_(n)OR⁷, EN, Hal, OCF₃, CF₃,     (CH₂)_(n)COOR⁷, ═O, A, (CH₂)_(n)CN, (CH₂)_(n)NR⁷SO₂R⁷,     (CH₂)_(n)SO₂NR⁷R⁸, (CH₂)_(n)N(C[Hal]₃)₂, (CH₂)_(n)CHOH(CH₂)_(n)OR⁷     or (CH₂)_(n)O(CH₂)_(m)OR⁷,     and R⁷, R⁸, A, n, m and Hal have the meanings indicated above, and     physiologically acceptable salts, derivatives, solvates, prodrugs     and stereoisomers thereof, including mixtures thereof in all ratios.

The invention furthermore very particularly preferably relates to all above-mentioned compounds of the formula I in which

-   R¹ denotes a straight-chain or branched alkyl group, mono-, bi- or     tricyclic cycloalkyl group, mono- or bicyclic cycloalkylalkyl group,     mono- or bicyclic aryl group, mono- or bicyclic arylalkyl group,     mono- or bicyclic heteroaryl group, mono- or bicyclic     heteroarylalkyl group which is unsubstituted or mono-, di- or     trisubstituted by (CH₂)_(n)OR⁷, EN, Hal, OCF₃, CF₃, ═O, A,     (CH₂)_(n)CN, (CH₂)_(n)NR⁷SO₂R⁷, (CH₂)_(n)SO₂NR⁷R⁸, -   R² H or a straight-chain or branched alkyl, cyclohexylmethyl,     cyclohexylethyl, benzyl or phenylethyl, each of which is     unsubstituted or mono-, di- or trisubstituted by (CH₂)_(n)OR⁷ or CI, -   R³ denotes a straight-chain or branched alkyl group, mono-, bi- or     tricyclic cycloalkyl group, mono- or bicyclic cycloalkylalkyl group,     mono- or bicyclic heterocycloalkyl group, mono- or bicyclic     heterocycloalkylalkyl group, mono- or bicyclic aryl group, mono- or     bicyclic arylalkyl group, mono- or bicyclic heteroaryl group or     mono- or bicyclic heteroarylalkyl group which is unsubstituted or     mono-, di- or trisubstituted by (CH₂)_(n)OR⁷, EN, Hal, OCF₃, CF₃,     (CH₂)_(n)COOR⁷, ═O, A, (CH₂)_(n)CN, (CH₂)_(n)NR⁷SO₂R⁷,     (CH₂)_(n)SO₂NR⁷R⁸, (CH₂)_(n)N(C[Hal]₃)₂, (CH₂)_(n)CHOH(CH₂)_(n)OR⁷     or (CH₂)_(n)O(CH₂)_(m)OR⁷     and R⁷, R⁸, A, n, m and Hal have the meanings given above, and     physiologically acceptable salts, derivatives, solvates, prodrugs     and stereoisomers thereof, including mixtures thereof in all ratios.

All above-mentioned preferred, particularly preferred and very particularly preferred meanings of the above radicals of the compounds of the formula I should be understood in such a way that these preferred, particularly preferred and very particularly preferred meanings or embodiments can be combined with one another in any possible combination to give compounds of the formula I and preferred, particularly preferred and very particularly preferred compounds of the formula I of this type are likewise explicitly disclosed hereby.

Very particular preference is also given to the following compounds of the formula I selected from the group consisting of:

1. (R)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 2. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methoxy- benzyl)-3-phenylpropionamide, 3. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(1-ethylpropyl)propionamide trifluoroacetate, 4. (R)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion-amide, 5. (S)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-(4-methoxyphenyl)propion-amide, 6. (S)-3-(4-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion-amide, 7. (S)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion-amide, 8. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(3,4- dimethoxyphenyl)ethyl]-3-phenylpropionamide, 9. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide, 10. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-phenethyl-3- phenylpropionamide, 11. (R)-N-[2-(4-chlorophenyl)ethyl]-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 12. (R)-N-[2-(2,4-dichlorophenyl)ethyl]-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 13. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide, 14. (S)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide, 15. (R)-N-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 16. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- sulfamoylbenzyl)propionamide, 17. (R)-N-(4-cyano-3-fluorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 18. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-(4-methoxyphenyl)propionamide, 19. (R)-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide trifluoroacetate, 20. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro- benzyl)-3-phenylpropionamide, 21. (R)-N-(3,4-difluorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 22. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 23. (R)-N-(2-bromo-4,5-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 24. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((1S,2R)-2- hydroxyindan-1-yl)-3-phenylpropionamide, 25. (R)-3-cyclohexyl-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 26. (R)-N-benzyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- methyl-3-phenylpropionamide, 27. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-methyl-3-phenylpropionamide, 28. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-propionamide, 29. (R)-N-(3,4-dichlorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 30. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- pyridin-4-ylmethylpropionamide, 31. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- pyridin-2-ylmethylpropionamide, 32. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide, 33. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isobutyl-3- phenylpropionamide, 34. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2,2- dimethylpropyl)-3-phenylpropionamide, 35. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methyl- butyl)-3-phenylpropionamide, 36. (R)-N-(4-tert-butylcyclohexyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 37. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2- methoxyethoxy)benzyl]-3-phenylpropionamide, 38. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2- hydroxyethoxy)benzyl]-3-phenylpropionamide, 39. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-ethyl- propyl)-3-phenylpropionamide, 40. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isopropyl-3- phenylpropionamide, 41. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-ethyl- butyl)-3-phenylpropionamide, 42. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-2- methylbutyl)-3-phenylpropionamide, 43. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-((S)-2-methylbutyl)propionamide, 44. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-methoxybenzyl amide, 45. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid isobutyl amide, 46. (2R,3R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanecarboxylic acid 4-fluoro-3-methoxybenzyl amide, 47. (R)-N-(2-benzo-1,3-dioxol-5-ylethyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 48. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(2- pyridin-4-ylethyl)propionamide, 49. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-hydroxypropionamide, 50. (R)-3-tert-butoxy-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 51. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3,4-dimethoxybenzyl amide, 52. (R)-N-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide, 53. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 54. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxy- benzyl)-3-phenylpropionamide, 55. (R)-3-(2-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 56. (R)-3-(4-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 57. 5-((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)furan-2-carboxylic acid methyl ester, 58. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- thiophen-2-ylmethylpropionamide, 59. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-ethoxy- pyridin-2-ylmethyl)-3-phenylpropionamide, 60. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 61. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-4-phenylbutyramide, 62. (1S,3S,4S)-4-((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionylamino)-3-hydroxycyclohexanecarboxylic acid methyl ester, 63. (R)-N-(3,5-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 64. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((R)-1- hydroxymethyl-3-methylbutyl)-3-phenylpropionamide, 65. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-1- hydroxymethyl-3-methylbutyl)-3-phenylpropionamide, 66. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methyl- cyclohexyl)-3-phenylpropionamide, 67. (2R,3R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanoic acid isobutyl amide, 68. R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((S)-2-methylbutyl) amide, 69. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[1-(4-fluoro-3-methoxyphenyl)cyclopropyl]propionamide, 70. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid [1-(4-fluoro-3-methoxyphenyl)cyclopropyl] amide, 71. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[1-(4-fluoro- 3-methoxyphenyl)cyclopropyl]-3-phenylpropionamide, 72. (R)-3,N-dicyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide, 73. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclohexyl amide, 74. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydropyran-4-yl)propionamide, 75. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (tetrahydropyran-4-yl) amide, 76. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-methyl- piperidin-4-yl)-3-phenylpropionamide, 77. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (1-methylpiperidin-4-yl) amide, 78. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 79. (R)-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 80. (R)-3-cyclohexyl-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 81. (R)-3-cyclohexyl-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 82. (R)-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 83. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)-1-(3- methoxyphenyl)ethyl]-3-phenylpropionamide, 84. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)-1-(3- methoxyphenyl)ethyl]-3-phenylpropionamide, 85. (S)-3-cyclohexyl-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 86. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(S)-1-(3-methoxyphenyl)ethyl]propionamide, 87. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(R)-1-(3-methoxyphenyl)ethyl]propionamide, 88. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydropyran-4-ylmethyl)propionamide, 89. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxy- propyl)-3-phenylpropionamide, 90. (S)-3-cyclohexyl-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 91. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-ylmethyl)propionamide, 92. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-methoxypropyl)propionamide, 93. (R)-3-cyclohexyl-2-{N′-[3-(3,4-dimethoxyphenyl)propionyl]- guanidino}-N-(4-fluoro-3-methoxybenzyl)propionamide, 94. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N- (4-fluoro-3-methoxybenzyl)propionamide, 95. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(4-methyl- pentanoyl)guanidino]propionamide, 96. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(indane-2- carbonyl)guanidino]propionamide, 97. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-dimethoxybenzyl amide, 98. (R)-3-cyclohexyl-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3- methoxybenzyl)propionamide, 99. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 100. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-[N′-(3-phenylpropionyl)- guanidino]propionamide, 101. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(3-phenyl- propionyl)guanidino]propionamide, 102. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-(N′-phenylacetyl- guanidino)propionamide, 103. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N- isobutylpropionamide, 104. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-N-(3,4- dimethoxybenzyl)-3-phenylpropionamide, 105. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-[N′-(3-phenylpropionyl)- guanidino]propionamide, 106. (R)-3-cyclohexyl-2-[N′-(indane-2-carbonyl)guanidino]-N-isobutyl- propionamide, 107. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(indane-2-carbonyl)guanidino]-3- phenylpropionamide, 108. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[3-(3,4-dimethoxyphenyl)- propionyl]guanidino}-3-phenylpropionamide, 109. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-isobutylpropionamide, 110. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-N- (3,4-dimethoxybenzyl)-3-phenylpropionamide, 111. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid isobutyl amide, 112. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-methoxybenzyl amide, 113. (R)-3-cyclohexyl-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-N- ((S)-2-methylbutyl)propionamide, 114. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-methoxy- phenyl)acetyl]guanidino}propionamide, 115. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-(N′-phenylacetyl- guanidino)propionamide, 116. (R)-3-cyclohexyl-N-isobutyl-2-[N′-(4-methylpentanoyl)guanidino]- propionamide, 117. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-(3-methoxyphenyl)acetyl]- guanidino}propionamide, 118. (R)-3-cyclohexyl-2-[N′-(2-cyclohexylacetyl)guanidino]-N-isobutyl- propionamide, 119. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(4-methylpentanoyl)guanidino]- 3-phenylpropionamide, 120. (R)-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(3,4-dimethoxybenzyl)- 3-phenylpropionamide, 121. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 122. (R)-N-(3-methoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 123. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 124. (R)-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide, 125. (R)-N-isobutyl-2-{N′-[2-(4-methoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 126. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(4-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 127. (R)-N-isobutyl-2-[N′-(2-phenoxyacetyl)guanidino]-3-phenylpropion-amide, 128. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(4-trifluoromethyl- phenyl)acetyl]guanidino}propionamide, 129. (R)-3-phenyl-N-(4-sulfamoylbenzyl)-2-{N′-[2-(4-trifluoromethoxy- phenyl)acetyl]guanidino}propionamide, 130. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(4-trifluoromethoxy- phenyl)acetyl]guanidino}propionamide, 131. (R)-N-isobutyl-2-[N′-(3-methylbutyryl)guanidino]-3-phenylpropion-amide, 132. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-[N′-(3-methylbutyryl)- guanidino]-3-phenylpropionamide, 133. (R)-2-[N′-(3-methylbutyryl)guanidino]-3-phenyl-N-(4-sulfamoyl- benzyl)propionamide, 134. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(3-methylbutyryl)guanidino]-3- phenylpropionamide, 135. (R)-4-methyl-2-[N′-(3-methylbutyryl)guanidino]-pentanoic acid 3,4- dimethoxybenzyl amide, 136. (R)-N-isobutyl-2-(N′-isobutyrylguanidino)-3-phenylpropionamide, 137. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N′-isobutyrylguanidino)-3- phenylpropionamide, 138. (R)-2-(N′-isobutyrylguanidino)-3-phenyl-N-(4-sulfamoylbenzyl)-propionamide, 139. (R)-N-(3,4-dimethoxybenzyl)-2-(N′-isobutyrylguanidino)-3-phenyl-propionamide, 140. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-methyl- sulfamoylbenzyl)-3-phenylpropionamide, 141. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 142. (R)-N-benzo-1,3-dioxol-5-ylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 143. (R)-N-(2,3-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 144. (R)-N-(3-bromobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 145. (R)-N-(3-chlorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 146. (R)-N-benzyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 147. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxy- phenyl)ethyl]-3-phenylpropionamide, 148. (S)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 149. (S)-3-(4-chlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 150. (R)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 151. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-(4-methoxy- phenyl)-2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 152. (R)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N′-[2-(3- phenoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 153. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N′-[2-(3- phenoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 154. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 155. (R)-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 156. (R)-3-cyclohexyl-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 157. (R)-3-cyclohexyl-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 158. (R)-2-[N′-(2-adamantan-1-ylacetyl)guanidino]-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide, 159. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-isobutyl- propionamide, 160. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide, 161. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide, 162. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-sulfamoylbenzyl)propionamide, 163. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclopropylmethyl amide, 164. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-sulfamoylbenzyl amide, 165. (R)-3-cyclohexyl-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 166. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(S)-1-(3-methoxyphenyl)ethyl]propionamide, 167. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(R)-1-(3-methoxyphenyl)ethyl]propionamide, 168. (R)-3-cyclohexyl-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 169. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-ylmethyl)propionamide, 170. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-methoxypropyl)propionamide, 171. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydrothiopyran-4-yl)propionamide, 172. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydrothiopyran-4-yl)propionamide, 173. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (tetrahydrothiopyran-4-yl) amide, 174. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-yl)propionamide, 175. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(1-methylpiperidin-4-yl)propionamide, 176. (R)-N-(5-chlorothiophen-2-ylmethyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 177. (R)-N-(5-chlorothiophen-2-ylmethyl)-3-cyclohexyl-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 178. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-fluoro-4- methoxybenzyl)-3-phenylpropionamide, 179. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-fluoro-4-methoxybenzyl)propionamide, 180. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-fluoro-4-methoxybenzyl amide, 181. (R)-3-cyclohexyl-N-(3,4-difluorobenzyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 182. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3,4-difluorobenzyl amide, 183. (R)-N-(6-chloropyridin-3-ylmethyl)-3-cyclohexyl-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 184. (R)-N-((S)-sec-butyl)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 185. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(trans-4-hydroxycyclohexyl)propionamide, 186. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (6-chloropyridin-3-ylmethyl) amide, 187. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluorobenzyl)propionamide, 188. (R)-3-cyclohexyl-N-cyclopropyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 189. (R)-3-cyclohexyl-N-cyclopentyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 190. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluorobenzyl amide, 191. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclopentyl amide, 192. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((S)-sec-butyl) amide, 193. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((R)-sec-butyl) amide, 194. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (trans-4-hydroxycyclohexyl) amide, 195. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (cis-4-hydroxycyclohexyl) amide, 196. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (S)-indan-1-yl amide amide, 197. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (R)-indan-1-ylamide amide, 198. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (4-methoxyindan-2-yl) amide, 199. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (5-methoxyindan-2-yl) amide, 200. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide, 201. (R)-3-cyclohexyl-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 202. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(cis-4-hydroxycyclohexyl)propionamide, 203. (R)-N-((R)-sec-butyl)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 204. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 205. (R)-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 206. (R)-3-cyclohexyl-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 207. (R)-3-cyclohexyl-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 208. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(S)-indan-1-ylpropionamide)propionamide, 209. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(R)-indan-1-ylpropionamide, 210. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-methoxyindan-2-yl)propionamide, 211. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(5-methoxyindan-2-yl)propionamide, 212. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 213. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3-methoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 214. (R)-3-cyclohexyl-2-{N′-[2-(4-fluoro-3-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 215. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3- methoxyphenyl)acetyl]guanidino}propionamide, 216. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4-methoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 217. (R)-3-cyclohexyl-2-{N′-[2-(3-fluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 218. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide, 219. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-[N′-(2-tetrahydro- pyran-4-ylacetyl)guanidino]propionamide, 220. (R)-3-cyclohexyl-N-isobutyl-2-[N′-(2-tetrahydropyran-4-ylacetyl)- guanidino]propionamide, 221. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-tetrahydro- pyran-4-ylacetyl)guanidino]propionamide, 222. (R)-3-cyclohexyl-2-{N′-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-(4-fluoro-3-methoxybenzyl)propionamide, 223. (R)-3-cyclohexyl-2-{N′-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 224. (R)-3-cyclohexyl-2-[N′-(3,3-dimethylbutyryl)guanidino]-N-(4-fluoro- 3-methoxybenzyl)propionamide, 225. (R)-3-cyclohexyl-2-[N′-(3,3-dimethylbutyryl)guanidino]-N-isobutyl- propionamide. 226. (R)-3-cyclohexyl-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 227. (R)-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 228. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)-3-phenylpropionamide, (R)-2-{N′-[2-(2- bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutyl- propionamide, 229. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-isobutylpropionamide, 230. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 231. (S)-2-benzyl-4-{N′-[(R)-1-(4-fluoro-3-methoxybenzylcarbamoyl)-2- phenylethyl]guanidino}-4-oxobutyric acid methyl ester, 232. (S)-2-benzyl-4-[N′-((R)-2-cyclohexyl-1-isobutylcarbamoylethyl)- guanidino]-4-oxobutyric acid methyl ester, 233. (S)-2-benzyl-4-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid methyl ester, 234. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 235. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N- isobutylpropionamide, 236. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 237. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-((S)-5-oxo- pyrrolidin-2-yl)acetyl]guanidino}propionamide, 238. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-((S)-5-oxopyrrolidin-2-yl)- acetyl]guanidino}propionamide, 239. (S)-2-benzyl-4-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid, 240. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(2,3,4-trimethoxy- phenyl)acetyl]guanidino}propionamide, 241. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-{N′-[2-(2,3,4- trimethoxyphenyl)acetyl]guanidino}propionamide, 242. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-(2,3,4-trimethoxyphenyl)- acetyl]guanidino}propionamide, 243. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2,3,4- trimethoxyphenyl)acetyl]guanidino}propionamide, 244. (R)-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide, 245. (R)-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 246. (R)-3-cyclohexyl-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N- isobutylpropionamide, 247. (R)-3-cyclohexyl-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 248. (R)-N-cyclobutyl-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 249. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclobutyl amide, 250. (R)-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 251. (R)-3-cyclohexyl-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N- isobutylpropionamide, 252. (R)-3-cyclohexyl-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 253. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-trifluoromethylbenzyl)propionamide, 254. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-trifluoromethylbenzyl amide, 255. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-trifluoromethylbenzyl)propionamide, 256. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-trifluoromethylbenzyl amide, 257. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-trifluoromethoxybenzyl)propionamide, 258. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-trifluoromethoxybenzyl amide, 259. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N′-[2-(4- fluoro-3-trifluoromethylphenyl)acetyl]guanidino}propionamide, 260. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N′-[2-(4- fluoro-3-trifluoromethylphenyl)acetyl]guanidino}propionamide, 261. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2,4,6- trifluorophenyl)acetyl]guanidino}propionamide, 262. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N′-[2- (2,4,6-trifluorophenyl)acetyl]guanidino}propionamide, 263. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N′-[2- (2,4,6-trifluorophenyl)acetyl]guanidino}propionamide, 264. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3- trifluoromethylphenyl)acetyl]guanidino}propionamide, 265. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-trifluoromethoxybenzyl)propionamide, 266. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-trifluoromethoxybenzyl amide, 267. (R)-N-[(S)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2- {N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 268. (R)-N-[(R)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2- {N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 269. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-4- methylpentanecarboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide, 270. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 271. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4- trifluoromethoxyphenyl)acetyl]guanidino}propionamide, 272. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-(1H-tetrazol-5-yl)benzyl]propionamide, 273. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-(1H-tetrazol-5-yl)benzyl amide, 274. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N- isobutylpropionamide, 275. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 276. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-fluoro-4-(1H-tetrazol-5-yl)benzyl]propionamide, 277. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-fluoro-4-(1H-tetrazol-5-yl)benzyl bamide, 278. (R)-2-{N′-[2-(2-bromo-4-trifluoromethylphenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 279. (R)-2-[N′-((2S,4R)-1-acetyl-4-methoxypyrrolidine-2-carbonyl)- guanidino]-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propion-amide, 280. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-piperidin-1- ylacetyl)guanidino]propionamide, 281. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-sulfamoylbenzyl)propionamide, 282. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-morpholin- 4-ylacetyl)guanidino]propionamide, 283. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4- sulfamoylphenyl)acetyl]guanidino}propionamide, 284. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide, 285. (R)-3-cyclohexyl-2-{N′-[2-(2-fluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 286. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl]acetyl}guanidino)propionamide, 287. (R)-2-{N′-[2-(3-cyanophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 288. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3- methanesulfonylaminophenyl)acetyl]guanidino}propionamide, 289. 4-[((R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionylamino)methyl]benzoic acid methyl ester, 290. 4-[((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester, 291. 4-[((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)methyl]benzoic acid methyl ester, 292. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propionamide, 293. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl amide, 294. 4-(2-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzylcarbamoyl)- ethyl]guanidino}-2-oxoethyl)-2-ethoxybenzoic acid ethyl ester, 295. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-pyridin-2-yl- acetyl)guanidino]propionamide, 296. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-isobutoxy- acetyl)guanidino]propionamide, 297. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-(1,2,3-thiadiazol-4-yl)benzyl amide, 298. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(3- sulfamoylbenzyl)propionamide, 299. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- (1,2,3-thiadiazol-4-yl)benzyl)propionamide, 300. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl]-3-phenylpropionamide, 301. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-tetrazol- 1-ylphenyl)acetyl]guanidino}propionamide, 302. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl- imidazol-1-yl)benzyl]-3-phenylpropionamide, 303. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(2-methylimidazol-1-yl)benzyl]propionamide, 304. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-(2-methylimidazol-1-yl)benzyl amide, 305. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- (1,2,4-triazol-1-yl)benzyl)propionamide, 306. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-1,2,4-triazol-1-ylbenzyl)propionamide, 307. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(1,2,4-triazol-1-yl)benzyl amide, 308. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 309. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-(5- hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 310. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 311. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 312. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 313. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5- hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 314. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-[4- (1H-tetrazol-5-yl)benzyl]propionamide, 315. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-1,2,3-thiadiazol-4-ylbenzyl)propionamide, 316. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(2-methyl-2H-pyrazol-3-yl)benzyl]propionamide, 317. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(2-methyl-2H-pyrazol-3-yl)benzyl amide, 318. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl- 2H-pyrazol-3-yl)benzyl]-3-phenylpropionamide, 319. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(1-methyl-1H-pyrazol-3-yl)benzyl]propionamide, 320. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(1-methyl-1H-pyrazol-3-yl)benzyl amide, 321. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(1-methyl- 1H-pyrazol-3-yl)benzyl]-3-phenylpropionamide, 322. (R)-2-{N′-[2-(4-chloro-2-fluorophenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 323. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-thiazol-2-ylbenzyl)propionamide, 324. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-thiazol-2-ylbenzyl amide, 325. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- thiazol-2-ylbenzyl)propionamide, 326. (R)-2-[N′-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 327. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 328. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 329. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 330. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3- (5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 331. (R)-2-[N′-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3- cyclohexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 332. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- [3-(1H-tetrazol-5-yl)benzyl]propionamide, 333. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[4-(2H- tetrazol-5-yl)phenyl]acetyl}guanidino)propionamide, 334. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-propyl- cyclohexyl)acetyl]guanidino}propionamide, 335. (R)-3-cyclohexyl-2-{N′-[2-(4-propylcyclohexyl)acetyl]guanidino}-N- [3-(1H-tetrazol-5-yl)benzyl]propionamide, 336. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3- (2H-tetrazol-5-yl)benzyl]-3-phenylpropionamide, 337. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-fluoro-3-(2H-tetrazol-5-yl)benzyl]propionamide, 338. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-fluoro-3-(2H-tetrazol-5-yl)benzyl amide, 339. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-{(S)-1-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 340. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- {(S)-1-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 341. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-{(S)-1-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 342. (R)-N-[4-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N′-[2- (3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 343. 4-[((R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionylamino)methyl]benzoic acid, 344. 3-[((R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl- propionylamino)methyl]benzoic acid methyl ester, 345. 3-[((R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester, 346. (R)-N-[3-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N′-[2- (3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 347. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[3-(2H- tetrazol-5-yl)phenyl]acetyl}guanidino)propionamide, 348. (R)-N-{1-[4-(bistrifluoromethylamino)phenyl]cyclopropyl}-3- cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propion-amide, 349. (R)-3-cyclohexyl-N-((R)-2,3-dihydroxypropyl)-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 350. (R)-3-cyclohexyl-N-((S)-2,3-dihydroxypropyl)-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

In the following moiety of the formula I, R² may also stand for a radical of a natural or non-natural amino acid.

Thus, R² can stand for the radicals of the following amino acids:

-   -   Natural amino acids: alanine, arginine, asparagine, aspartic         acid, cysteine, glutamine, glutamic acid, glycine, histidine,         isoleucine, leucine, lysine, methionine, ornithine,         phenylalanine, proline, serine, threonine, tryptophan, tyrosine         and valine     -   Non-natural amino acids, such as, for example,         cyclopropylglycine, cyclobutylglycine, cyclopentylglycine,         cyclohexylglycine, 3-oxetanylglycine, 3-oxetanylglycine,         tetrahydrofuran-3-ylglycine, tetrahydrofuran-2-ylglycine,         ethylsulfanylmethylglycine, 2-methylsulfanylethylglycine,         1-methylsulfanylethylglycine, norvaline, aminobutyric acid,         tert-leucine, norleucine, naphthylalanine, O-methylserine,         O-ethylserine and the like.

If the above-mentioned amino acids can occur in a plurality of enantiomeric forms, all these forms and also mixtures thereof (for example DL forms) are included above and below.

Furthermore, the abbreviations have the following meanings:

Boc ter-butoxycarbonyl

CBZ benzyloxycarbonyl

DNP 2,4-dinitrophenyl

FMOC 9-fluorenylmethoxycarbonyl

imi-DNP 2,4-dinitrophenyl in the 1-position of the imidazole ring

OMe methyl ester

POA phenoxyacetyl

DCCl dicyclohexylcarbodiimide

HOBt 1-hydroxybenzotriazole

Hal denotes fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

—(C═O)— or ═O denotes carbonyl oxygen and stands for

or an oxygen atom bonded to a carbon atom by means of a double bond

A stands for alkyl, alkenyl, alkynyl or cycloalkyl.

Alkyl is a saturated, unbranched (linear) or branched hydrocarbon chain and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. Alkyl preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, linear or branched heptyl, octyl, nonyl or decyl, further preferably, for example, trifluoromethyl.

With regard to the present invention, alkyl additionally also denotes cyclo-alkyl.

Alkenyl denotes an unsaturated hydrocarbon chain which has at least one double bond, preferably methenyl, ethenyl, propenyl, butenyl, pentenyl or hexenyl, furthermore branched alkenyl.

Alkynyl denotes an unsaturated hydrocarbon chain which has at least one triple bond, preferably methynyl, ethynyl, propynyl, butynyl, pentynyl or hexynyl, furthermore branched alkynyl.

Cyclic alkyl or cycloalkyl is a saturated cyclic hydrocarbon chain and has 3-10, preferably 3-7 C atoms and preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl also denotes a partially unsaturated cyclic akyl, such as, for example, cyclohexenyl or cyclohexynyl.

Aryl denotes an aromatic or fully unsaturated cyclic hydrocarbon chain, for example unsubstituted phenyl, naphthyl or biphenyl, furthermore preferably phenyl, naphthyl or biphenyl, each of which is mono-, di- or trisubstituted by, for example, A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfon-amido, dimethylsulfonamido, phenylsulfonamido, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl.

Mono- or bicyclic saturated, unsaturated or aromatic heterocycle preferably denotes unsubstituted or mono-, di- or trisubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benz-oxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated and also denote, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxyl)phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Heterocycle furthermore denotes, for example, 2-oxopiperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxoazepan-1-yl), 2-hydroxy-6-oxopiperazin-1-yl, 2-methoxy-6-oxopiperazin-1-yl or 2-azabicyclo[2.2.2]octan-3-on-2-yl.

Heterocycloalkyl here denotes a fully hydrogenated or saturated heterocycle, heterocycloaklenyl (one or more double bonds) or heterocycloaklynyl (one or more triple bonds) denotes a partially or incompletely hydrogenated or unsaturated heterocycle, heteroaryl denotes an aromatic or fully unsaturated heterocycle.

Cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, heterocycloalkylalkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl means that the respective ring system are bonded via an alkyl, alkenyl or alkynyl radical.

Thus, cycloalkylalkenyl having 5-12 C atoms denotes, for example, cyclopentylmethenyl, cyclohexylmethenyl, cyclohexylethenyl, cyclohexylpropenyl or cyclohexylbutenyl and cycloalkylalkynyl having 5-12 C atoms, denotes, for example, cyclopentylmethynyl, cyclohexylmethynyl, cyclohexylethynyl, cyclohexylpropynyl or cyclohexylbutynyl.

OA denotes alkoxy and is preferably methoxy, furthermore also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

All physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds, including mixtures thereof in all ratios, are also in accordance with the invention.

Compounds of the general formula I may contain one or more centres of chirality, so that all stereoisomers, enentiomers, diastereomers, etc., of the compounds of the general formula I are also claimed in the present invention.

The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.

Compounds of the formula I according to the invention may be chiral owing to their molecular structure and may accordingly occur in various enantiomeric forms. They may therefore be in racemic or optically active form. Since the pharmaceutical efficacy of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product, but also even the intermediates, may be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or already employed as such in the synthesis.

Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds according to the invention and also so-called prodrug compounds. Prodrug compounds are taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars or oligopeptides and which are rapidly cleaved or liberated in the organism to form the effective compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

Suitable acid-addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methyl-sulfonates or p-toluenesulfonates.

Very particular preference is given to the hydrochlorides, the trifluoro-acetates or the bistrifluoroacetates of the compounds according to the invention.

Solvates of the compounds of the formula I are taken to mean adductions of inert solvent molecules onto the compounds of the formula I which form owing to their mutual attractive force. Solvates are, for example, hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. addition compounds with alcohols, such as, for example, with methanol or ethanol.

It is furthermore intended that a compound of the formula I includes iso-tope-labelled forms thereof. An isotope-labelled form of a compound of the formula I is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of the formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ²H, ³H, ¹³O, ¹⁴O, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I, a prodrug thereof or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention. An isotope-labelled compound of the formula I can be used in a number of beneficial ways. For example, an isotope-labelled compound of the formula I into which, for example, a radioisotope, such as ³H or ¹⁴C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays. These radioisotopes, i.e. tritium (³H) and carbon-14 (¹⁴O), are particularly preferred owing to their simple preparation and excellent detectability. Incorporation of heavier isotopes, for example deuterium (²H), into a compound of the formula I has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in-vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labelled compound of the formula I can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant with a readily available isotope-labelled reactant.

In order to manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect, deuterium (²H) can also be incorporated into a compound of the formula I. The primary kinetic isotope effect is a change in the rate of a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate in rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom in a non-exchangeable position, rate differences of k_(M)/k_(D)=2-7 are typical. If this rate difference is successfully applied to a compound of the formula I that is susceptible to oxidation, the profile of this compound in vivo can thereby be drastically modified and result in improved pharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilled in the art attempts to optimise pharmacokinetic parameters while retaining desirable in-vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In-vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of the formula I with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of the compounds of the formula I are thereby obtained and can be expressed quantitatively in terms of increases in the in-vivo half-life (T/2), concentration at maximum therapeutic effect (C_(max)), area under the dose response curve (AUC), and F; and in terms of reduced clearance, dose and costs of materials.

The following is intended to illustrate the above: a compound of the formula I which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.

The replacement of hydrogen by deuterium in a compound of the formula I can also be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the undesired metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange is given, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33(10), 2927-2937, 1994, and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

The invention also relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of two stereoisomeric compounds. However, preference is also given to mixtures of two or more compounds of the formula I.

The invention additionally relates to a process for the preparation of the compounds of the formula I, characterised in that

-   a) a compound of the formula VII,

-   -   in which R¹ has the meanings indicated above,     -   is obtained by acylation of a pyrazole-1-carboxamidine of the         formula XI

-   -   using an acid of the formula X or an acid derivative of the         formula Xa using auxiliary bases or coupling reagents which are         usual in such reactions, by methods known from the literature,

-   -   in which R¹ has the meanings indicated above and X denotes a         halogen, alkyl- or aryloxycarbonyloxy, such as, for example,         ethoxycarbonyloxy or p-nitrophenyloxycarbonyloxy,     -   and a compound of the formula VIII

-   -   in which R¹ has the meanings indicated above and R¹¹ denotes a         protecting group for amines or imines, is obtained by reacting a         guanidine of the formula IX,

-   -   in which R¹¹ has the meanings indicated above, with an acid of         the formula X or an activated acid derivative of the formula Xa,

-   -   in which R¹ and X have the meanings indicated above,     -   and a compound of the formula III,

-   -   in which R¹ and R¹¹ have the meanings indicated above and L         denotes a leaving group, such as, for example, a 1-pyrrazolyl or         trifluoromethylsulfonylamino group, is prepared by either     -   in the case where L denotes a 1-pyrazolyl group, introducing a         protecting group R¹¹ into a compound of the formula VII by the         usual processes known from the literature,     -   or, in the case where L denotes a trifluoromethylsulfonylamino         group, preparing a compound of the formula III by reaction of a         compound of the formula VIII with trifluoromethanesulfonic         anhydride by the usual methods known from the literature,     -   and a compound of the formula II,

-   -   in which R² and R³ have the meanings indicated above, is         prepared by preparing a compound of the formula IV,

-   -   in which R², R³ and R¹¹ have the meanings indicated above, by         coupling an amino acid of the formula V,

-   -   in which R³ and R¹¹ have the meanings indicated above, to an         amine of the formula VI,         H₂N—R³  VI     -   in which R³ has the meanings indicated above, by processes known         from the literature using coupling reagents which are usual in         such reactions,     -   and a compound of the formula II is prepared by removing R¹¹         from a compound of the formula IV by processes known from the         literature,     -   and then obtaining a compound of the formula Ia

-   -   in which R¹, R², R³ and R¹¹ have the meanings indicated above,         by reaction of an amine of the formula II with an acylguanidine         of the formula III,     -   and a compound of the formula I is obtained by removing R¹¹, a         protecting group for amines or imines, such as a         tert-butyloxycarbonyl (BOC group) or benzyloxycarbonyl group (Z         group), from a compound of the formula Ia, by processes known         from the literature. or

-   b) a compound of the formula VII is reacted with an amine of the     formula II, or

-   c) the base of a compound of the formula I is converted into one of     its salts by treatment with an acid, or

-   d) an acid of a compound of the formula I is converted into one of     its salts by treatment with a base.

The synthesis of the compounds according to the invention is summarised in Scheme 1.

It is also possible to carry out the reactions stepwise in each case and to modify the sequence of the linking reactions of the building blocks with adaptation of the protecting-group concept.

The starting materials or starting compounds are generally known. If they are novel, they can be prepared by methods known per se.

If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula I.

The compounds of the formula I are preferably obtained by liberating them from their functional derivatives by solvolysis, in particular by hydrolysis, or by hydrogenolysis. Preferred starting materials for the solvolysis or hydrogenolysis are those which contain correspondingly protected amino, carboxyl and/or hydroxyl groups instead of one or more free amino, carboxyl and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom which is connected to an N atom. Preference is furthermore given to starting materials which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group. Preference is also given to starting materials which carry a protected carboxyl group instead of a free carboxyl group. It is also possible for a plurality of identical or different protected amino, carboxyl and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is generally known and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl groups, furthermore unsubstituted or substituted aryl (for example 2,4-dinitophenyl) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino-protecting groups are removed after the desired reaction or reaction sequence, their type and size is, in addition, not crucial, but preference is given to those having 1-20, in particular 1-8, C atoms. The term “acyl group” is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxy-carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Exam-pies of such acyl groups are alkanoyl, such as acteyl, propionyl, buturyl, aralkanoyl, such as phenylacetyl, aroyl, such as benzoyl or toluyl, aryoxyaklkanoyl, such as phenoxyacetyl, alkyoxycarbonyyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycaronyl, aralkoxycarbonyl. such as CBZ, 4-methoxybenzyloxycarbonyl or FMOC. Preferred acyl groups are CBZ, FMOC, benzyl and acetyl.

The term “acid-protecting group” or “carboxyl-protecting group” is likewise generally known and relates to groups which are suitable for protecting a —COOH group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. The use of esters instead of the free acids, for example of substituted and unsubstituted alkyl esters (such as methyl, ethyl, tert-butyl and substituted derivatives thereof), of substituted and unsubstituted benzyl esters or silyl esters, is typical. The type and size of the acid-protecting groups is not crucial, but preference is given to those having 1-20, in particular 1-10, C atoms.

The term “hydroxyl-protecting group” is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The their type and size of the hydroxyl-protecting groups is not crucial, but preference is given to those having 1-20, in particular 1-10, C atoms. Examples of hyrdoxyl-protecting groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, where benzyl and acetyl are preferred.

Further typical examples of amino-, acid- and hydroxyl-protecting groups are found, for example, in “Greene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2007.

The functional derivatives of the compounds of the formula I to be used as starting materials can be prepared by known methods of amino-acid and peptide synthesis, as described, for example, in the said standard works and patent applications.

The compounds of the formula I are liberated from their functional derivatives, depending on the protecting group used, for example, with the aid of strong acids, advantageously using trifluoroacetic acid or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic acids, such as trichloroacetic acid, or sulfonic acids, such as benzoyl- or p-toluenesulfonic acid. The presence of an additional inert solvent and/or a catalyst is possible, but is not always necessary.

Depending on the respective synthetic route, the starting materials can optionally be reacted in the presence of an inert solvent.

Suitable inert solvents are, for example, heptane, hexane, petroleum ether, DMSO, benzene, toluene, xylene, trichloroethylene-, 1,2-dichloroethanecarbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether (preferably for substitution on the indole nitrogen), tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethy-I ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such as acetonitrile; esters, such as ethyl acetate, carboxylic acids or acid anhydrides, such as, for example, such as acetic acid or acetic anhydride, nitro compounds, such as nitromethane or nitrobenzene, optionally also mixtures of the said solvents with one another or mixtures with water.

The amount of solvent is not crucial; 10 g to 500 g of solvent can preferably be added per g of the compound of the formula I to be reacted.

It may be advantageous to add an acid-binding agent, for example an alkali metal or alkaline-earth metal hydroxide, carbonate or bicarbonate or other alkali or alkaline-earth metal salts of weak acids, preferably a potassium, sodium or calcium salt, or to add an organic base, such as, for example, on triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.

The resultant compounds according to the invention can be separated from the corresponding solution in which they are prepared (for example by centrifugation and washing) and can be stored in another composition after separation, or they can remain directly in the preparation solution.

The resultant compounds according to the invention can also be taken up in desired solvents for the particular use.

Suitable reaction temperatures are temperatures from 0 to 40° C., preferably 5 to 25° C.

The reaction duration depends on the reaction conditions selected. In general, the reaction duration is 0.5 hour to 10 days, preferably 1 to 24 hours. On use of a microwave, the reaction time can be reduced to values of 1 to 60 minutes.

The compounds of the formula I and also the starting materials for their preparation are, in addition, prepared by known methods, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), for example under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants known per se, which are not described here in greater detail.

Conventional work-up steps, such as, for example, addition of water to the reaction mixture and extraction, enable the compounds to be obtained after removal of the solvent. It may be advantageous, for further purification of the product, to follow this with a distillation or crystallisation or to carry out a chromatographic purification.

An acid of the formula I can be converted into the associated addition salt using a base, for example by reaction of equivalent amounts of the acid and base in an inert solvent, such as ethanol, and inclusive evaporation. Suitable bases for this reaction are, in particular, those which give physiologically acceptable salts. Thus, the acid of the formula I can be converted into the corresponding metal salt, in particular alkali or alkaline-earth metal salt, using a base (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or into the corresponding ammonium salt. Organic bases which give physiologically acceptable salts, such as, for example, ethanolamine, are also suitable for this reaction.

On the other hand, a base of the formula I can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and acid in an inert solvent, such as ethanol, with subsequent evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemom- and disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula I.

It has been found that the compounds of the formula I are well tolerated and have valuable pharmacological properties, since they selectively inhibit aspartyl proteases and in particular cathepsin D.

The invention therefore furthermore relates to the use of compounds according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of diseases which are caused, promoted and/or propagated by cathepsin D and/or by cathepsin D-promoted signal transduction.

The invention thus also relates, in particular, to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states.

Particular preference is given, in particular, to physiological and/or pathophysiological states which are connected to cathepsin D.

Physiological and/or pathophysiological states are taken to mean physiological and/or pathophysiological states which are medically relevant, such as, for example, diseases or illnesses and medical disorders, complaints, symptoms or complications and the like, in particular diseases.

The invention furthermore relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of arthrosis, traumatic cartilage injuries and arthritis, in particular rheumatoid arthritis.

The invention furthermore relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of Alzheimer's disease, Huntington's disease, mucolipidosis, cancer, in particular breast cancer, contact dermatitis, late-onset hypersensitivity reaction, inflammation, endometriosis, scarring, benign prostate hyperplasia, osteosarcoma, rickets, skin diseases, such as, for example, psoriasis, immunological diseases, autoimmune diseases and immunodeficiency diseases.

In this connection, brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynaecological cancer, thyroid cancer, lymphomas, chronic leukaemia and acute leukaemia are to be regarded as cancerous diseases, all of which usually count amongst the group of hyperproliferative diseases.

Pain is a complex sensory perception which, as an acute event, has the character of a warning and control signal, but as chronic pain has lost this and in this case (as chronic pain syndrome) should be regarded and treated today as an independent syndrome. Hyperalgesia is the term used in medicine for excessive sensitivity to pain and reaction to a stimulus which is usually painful. Stimuli which can trigger pain are, for example, pressure, heat, cold or inflammation. Hyperalgesia is a form of hyperaesthesia, the generic term for excessive sensitivity to a stimulus. Allodynia is the term used in medicine for the sensation of pain which is triggered by stimuli which do not usually cause pain.

The invention thus furthermore relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, selected from the group consisting of pain, allodynia and hyperalgesia.

The invention thus particularly preferably relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, selected from the group consisting of arthrosis, traumatic cartilage injuries, arthritis, pain, allodynia and hyperalgesia.

It is intended that the medicaments disclosed above include a corresponding use of the compounds according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of the above physiological and/or pathophysiological states.

It is additionally intended that the medicaments disclosed above include a corresponding method for the treatment and/or prophylaxis of the above physiological and/or pathophysiological states in which at least one compound according to the invention is administered to a patient in need of such a treatment.

The compounds according to the invention preferably exhibit an advantageous biological activity which can easily be demonstrated in enzyme assays and animal experiments, as described in the examples. In such enzyme-based assays, the antibodies according to the invention preferably exhibit and cause an inhibiting effect, which is usually documented by IC₅₀ values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.

The compounds according to the invention can be administered to humans or animals, in particular mammals, such as apes, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in the combating of the above-mentioned diseases. They can furthermore be used as diagnostic agents or as reagents. Furthermore, compounds according to the invention can be used for the isolation and investigation of the activity or expression of cathepsin D. In addition, they are particularly suitable for use in diagnostic methods for diseases in connection with disturbed cathepsin D activity. The invention therefore furthermore relates to the use of the compounds according to the invention for the isolation and investigation of the activity or expression of cathepsin D or as binders and inhibitors of cathepsin D.

For diagnostic purposes, the compounds according to the invention can, for example, be radioactively labelled. Examples of radioactive labels are ³H, ¹⁴C, ²³¹I and ¹²⁵I. A preferred labelling method is the iodogen method (Fraker et al., 1978). In addition, the compounds according to the invention can be labelled by enzymes, fluorophores and chemophores. Examples of enzymes are alkaline phosphatase, β-galactosidase and glucose oxidase, an example of a fluorophore is fluorescein, an example of a chemophore is luminol, and automated detection systems, for example for fluorescent colorations, are described, for example, in U.S. Pat. No. 4,125,828 and U.S. Pat. No. 4,207,554.

The compounds of the formula I can be used for the preparation of pharmaceutical preparations, in particular by non-chemical methods. In this case, they are brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or adjuvant and optionally in combination with one or more further active compound(s).

The invention therefore furthermore relates to pharmaceutical preparations comprising at least one compound of the formula I and/or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. In particular, the invention also relates to pharmaceutical preparations which comprise further excipients and/or adjuvants, and also to pharmaceutical preparations which comprise at least one further medicament active compound.

In particular, the invention also relates to a process for the preparation of a pharmaceutical preparation, characterised in that a compound of the formula I and/or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, is brought into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant and optionally with a further medicament active compound.

The pharmaceutical preparations according to the invention can be used as medicaments in human or veterinary medicine. The patient or host can belong to any mammal species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental investigations, where they provide a model for the treatment of a human disease.

Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils (such as sunflower oil or cod-liver oil), benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc, lanolin or Vaseline. Owing to his expert knowledge, the person skilled in the art is familiar with which adjuvants are suitable for the desired medicament formulation. Besides solvents, for example water, physiological saline solution or alcohols, such as, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose or mannitol solutions, or a mixture of the said solvents, gel formers, tablet assistants and other active-ingredient carriers, it is also possible to use, for example, lubricants, stabilisers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, antioxidants, dispersants, antifoams, buffer substances, flavours and/or aromas or flavour correctants, preservatives, solubilisers or dyes. If desired, preparations or medicaments according to the invention may comprise one or more further active compounds, for example one or more vitamins.

If desired, preparations or medicaments according to the invention may comprise one or more further active compounds and/or one or more action enhancers (adjuvants).

The terms “pharmaceutical formulation” and “pharmaceutical preparation” are used as synonyms for the purposes of the present invention.

As used here, “pharmaceutically tolerated” relates to medicaments, precipitation reagents, excipients, adjuvants, stabilisers, solvents and other agents which facilitate the administration of the pharmaceutical preparations obtained therefrom to a mammal without undesired physiological side effects, such as, for example, nausea, dizziness, digestion problems or the like.

In pharmaceutical preparations for parenteral administration, there is a requirement for isotonicity, euhydration and tolerability and safety of the formulation (low toxicity), of the adjuvants employed and of the primary packaging. Surprisingly, the compounds according to the invention preferably have the advantage that direct use is possible and further purification steps for the removal of toxicologically unacceptable agents, such as, for example, high concentrations of organic solvents or other toxicologically unacceptable adjuvants, are thus unnecessary before use of the compounds according to the invention in pharmaceutical formulations.

The invention particularly preferably also relates to pharmaceutical preparations comprising at least one compound according to the invention in precipitated non-crystalline, precipitated crystalline or in dissolved or suspended form, and optionally excipients and/or adjuvants and/or further pharmaceutical active compounds.

The compounds according to the invention preferably enable the preparation of highly concentrated formulations without unfavourable, undesired aggregation of the compounds according to the invention occurring. Thus, ready-to-use solutions having a high active-ingredient content can be prepared with the aid of compounds according to the invention with aqueous solvents or in aqueous media.

The compounds and/or physiologically acceptable salts and solvates thereof can also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations.

Aqueous preparations can be prepared by dissolving or suspending compounds according to the invention in an aqueous solution and optionally adding adjuvants. To this end, defined volumes of stock solutions comprising the said further adjuvants in defined concentration are advantageously added to a solution or suspension having a defined concentration of compounds according to the invention, and the mixture is optionally diluted with water to the pre-calculated concentration. Alternatively, the adjuvants can be added in solid form. The amounts of stock solutions and/or water which are necessary in each case can subsequently be added to the aqueous solution or suspension obtained. Compounds according to the invention can also advantageously be dissolved or suspended directly in a solution comprising all further adjuvants.

The solutions or suspensions comprising compounds according to the invention and having a pH of 4 to 10, preferably having a pH of 5 to 9, and an osmolality of 250 to 350 mOsmol/kg can advantageously be prepared. The pharmaceutical preparation can thus be administered directly substantially without pain intravenously, intra-arterially, intra-articularly, subcutaneously or percutaneously. In addition, the preparation may also be added to infusion solutions, such as, for example, glucose solution, isotonic saline solution or Ringer's solution, which may also contain further active compounds, thus also enabling relatively large amounts of active compound to be administered.

Pharmaceutical preparations according to the invention may also comprise mixtures of a plurality of compounds according to the invention.

The preparations according to the invention are physiologically well tolerated, easy to prepare, can be dispensed precisely and are preferably stable with respect to assay, decomposition products and aggregates throughout storage and transport and during multiple freezing and thawing processes. They can preferably be stored in a stable manner over a period of at least three months to two years at refrigerator temperature (2-8° C.) and at room temperature (23-27° C.) and 60% relative atmospheric humidity (R.H.).

For example, the compounds according to the invention can be stored in a stable manner by drying and when necessary converted into a ready-to-use pharmaceutical preparation by dissolution or suspension. Possible drying methods are, for example, without being restricted to these examples, nitrogen-gas drying, vacuum-oven drying, lyophilisation, washing with organic solvents and subsequent air drying, liquid-bed drying, fluidised-bed drying, spray drying, roller drying, layer drying, air drying at room temperature and further methods.

The term “effective amount” denotes the amount of a medicament or of a pharmaceutical active compound which causes in a tissue, system, animal or human a biological or medical response which is sought or desired, for example, by a researcher or physician.

In addition, the term “therapeutically effective amount” denotes an amount which, compared with a corresponding subject who has not received this amount, has the following consequence: improved treatment, healing, prevention or elimination of a disease, syndrome, disease state, complaint, disorder or prevention of side effects or also a reduction in the progress of a disease, complaint or disorder. The term “therapeutically effective amount” also encompasses the amounts which are effective for increasing normal physiological function.

On use of preparations or medicaments according to the invention, the compounds according to the invention and/or physiologically acceptable salts and solvates thereof are generally used analogously to known, commercially available preparations or preparations, preferably in dosages of between 0.1 and 500 mg, in particular 5 and 300 mg, per use unit. The daily dose is preferably between 0.001 and 250 mg/kg, in particular 0.01 and 100 mg/kg, of body weight. The preparation can be administered one or more times per day, for example two, three or four times per day.

However, the individual dose for a patient depends on a large number of individual factors, such as, for example, on the efficacy of the particular compound used, on the age, body weight, general state of health, sex, nutrition, on the time and method of administration, on the excretion rate, on the combination with other medicaments and on the severity and duration of the particular disease.

A measure of the uptake of a medicament active compound in an organism is its bioavailability. If the medicament active compound is delivered to the organism intravenously in the form of an injection solution, its absolute bioavailability, i.e. the proportion of the pharmaceutical which reaches the systemic blood, i.e. the major circulation, in unchanged form, is 100%. In the case of oral administration of a therapeutic active compound, the active compound is generally in the form of a solid in the formulation and must therefore first be dissolved in order that it is able to overcome the entry barriers, for example the gastrointestinal tract, the oral mucous membrane, nasal membranes or the skin, in particular the stratum corneum, or can be absorbed by the body. Data on the pharmacokinetics, i.e. on the bioavailability, can be obtained analogously to the method of J. Shaffer et al., J. Pharm. Sciences, 88 (1999), 313-318.

Furthermore, medicaments of this type can be prepared by means of one of the processes generally known in the pharmaceutical art.

Medicaments can be adapted for administration via any desired suitable route, for example by the oral (including buccal or sublingual), rectal, pulmonary, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and in particular intra-articular) routes. Medicaments of this type can be prepared by means of all processes known in the pharmaceutical art by, for example, combining the active compound with the excipient(s) or adjuvant(s).

Parenteral administration is preferably suitable for administration of the medicaments according to the invention. In the case of parenteral administration, intra-articular administration is particularly preferred.

The invention thus preferably also relates to the use of a pharmaceutical preparation according to the invention for intra-articular administration in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of arthrosis, traumatic cartilage injuries, arthritis, pain, allodynia or hyperalgesia.

Intra-articular administration has the advantage that the compound according to the invention can be administered directly into the synovial fluid in the vicinity of the joint cartilage and is also able to diffuse from there into the cartilage tissue. Pharmaceutical preparations according to the invention can thus also be injected directly into the joint gap and thus develop their action directly at the site of action as intended. The compounds according to the invention are also suitable for the preparation of medicaments to be administered parenterally having slow, sustained and/or controlled release of active compound. They are thus also suitable for the preparation of delayed-release formulations, which are advantageous for the patient since administration is only necessary at relatively large time intervals.

The medicaments adapted to parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buff-ers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood or synovial fluid of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can comprise suspension media and thickeners. The formulations can be delivered in single-dose or multi-dose containers, for example sealed ampoules and vials, and stored in the freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary. Injection solutions and suspensions prepared in accordance with the formulation can be prepared from sterile powders, granules and tablets.

The compounds according to the invention can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds according to the invention can also be coupled to soluble polymers as targeted medicament excipients. Such polymers can encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds according to the invention can furthermore be coupled to a class of biodegradable polymers which are suitable for achieving slow release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, polylactic-co-glycolic acid, polymers, such as conjugates between dextran and methacrylates, polyphosphoesters, various polysaccharides and polyamines and poly-ε-caprolactone, albumin, chitosan, collagen or modified gelatine and crosslinked or amphipathic block copolymers of hydrogels.

Suitable for enteral administration (oral or rectal) are, in particular, tablets, dragees, capsules, syrups, juices, drops or suppositories, and suitable for topical use are ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols, such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or mixtures thereof with one another and/or with water) or powders. Also particularly suitable for topical uses are liposomal preparations.

In the case of formulation to give an ointment, the active compound can be employed either with a paraffinic or a water-miscible cream base. Alternatively, the active compound can be formulated to a cream with an oil-in-water cream base or a water-in-oil base.

Medicaments adapted to transdermal administration can be delivered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active compound can be supplied from the plaster by means of iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).

It goes without saying that, besides the constituents particularly mentioned above, the medicaments according to the invention may also comprise other agents usual in the art with respect to the particular type of pharmaceutical formulation.

The invention also relates to a set (kit) consisting of separate packs of

-   a) an effective amount of a compound of the formula I and/or     physiologically acceptable salts, derivatives, solvates, prodrugs     and stereoisomers thereof, including mixtures thereof in all ratios,     and -   b) an effective amount of a further medicament active compound.

The set comprises suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set may, for example, comprise separate ampoules each containing an effective amount of a compound of the formula I and/or pharmaceutically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active compound in dissolved or lyophilised form.

Furthermore, the medicaments according to the invention can be used in order to provide additive or synergistic effects in certain known therapies and/or can be used in order to restore the efficacy of certain existing therapies.

Besides the compounds according to the invention, the pharmaceutical preparations according to the invention may also comprise further medicament active compounds, for example for use in the treatment of arthrosis, other cathepsin D inhibitors, NSAIDS, Cox-2 inhibitors, glucocorticoids, hyaluronic acid, azathioprine, methotrexate, anti-CAM antibodies, such as, for example, anti-ICAM-1 antibody, FGF-18. For the treatment of the other diseases mentioned, the pharmaceutical preparations according to the invention may also, besides the compounds according to the invention, comprise further medicament active compounds which are known to the person skilled in the art in the treatment thereof.

The cancer treatment disclosed here can be carried out as therapy with a compound of the present invention or in combination with an operation, irradiation or chemoherapy. Chemotherapy of this type can include the use of one or more active compounds of the following categories of antitumour active compounds:

(i) antiproliferative/antineoplastic/DNA-damaging active compounds and combinations thereof, as used in medical oncology, such as alkylating active compounds (for example cis-platin, parboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthra-cyclines, such as adriamycin, bleomycin, doxorubicin, daunomycin, epi-rubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic active compounds (for example vinca alkaloids, such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids, such as taxol and taxotere); topoisomerase inhibitors (for example epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell-differentiating active compounds (for example all-trans-retinoic acid, 13-cis-retinoic acid and fenretinide); (ii) cytostatic active compounds, such as anti-oestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor regulators (for example fulvestrant), anti-androgens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progesterones (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase, such as finasteride; (iii) active compounds which inhibit cancer invasion (for example metalloproteinase inhibitors, like marimastat, and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example growth factor antibodies, growth factor receptor antibodies, for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (Cl 1033), for example inhibitors of the platelet-derived growth factor family and, for example, inhibitors of the hepatocyte growth factor family; (v) anti-angiogenic active compounds, such as those which inhibit the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds which have been published in the international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds which act by another mechanism (for example linomide, inhibitors of integrin αvβ3 function and angiostatin); (vi) vessel-destroying agents, such as combretastatin A4 and compounds which have been published in the international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, for example those directed to the targets mentioned above, such as ISIS 2503, an anti-Ras antisense; (viii) gene therapy approaches, including, for example, approaches for replacement of abnormal, modified genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT approaches (gene-directed enzyme pro-drug therapy), such as those which use cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and approaches which increase the tolerance of a patient to chemotherapy or radiotherapy, such as multi-drug resistance therapy; and (ix) immunotherapy approaches, including, for example, ex-vivo and in-vivo approaches for increasing the immunogenicity of tumour cells of a patient, such as transfection with cytokines, such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches for decreasing T-cell anergy, approaches using transfected immune cells, such as cytokine-transfected dendritic cells, approaches for use of cytokine-transfected tumour cells and approaches for use of anti-idiotypic antibodies.

The medicaments from Table 1 can preferably, but not exclusively, be combined with the compounds of the formula 1.

TABLE 1 Alkylating active Cyclophosphamide Lomustine compounds Busulfan Procarbazine Ifosfamide Altretamine Melphalan Estramustine phosphate Hexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucil Temozolomide Dacarbazine Semustine Carmustine Platinum active Cisplatin Carboplatin compounds Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine Tomudex Gemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-Fluorouracil Fludarabine Floxuridine Pentostatin 2-Chlorodesoxyadenosine Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine (Bioenvision) 2-Fluorodesoxycytidine Irofulven (MGI Pharrna) Methotrexate DMDC (Hoffmann-La Roche) Idatrexate Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors Epirubicin Exatecan mesylate (Daiichi) Etoposide Quinamed (ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma-Tau) Irinotecan (CPT-11) Diflomotecan (Beaufour- 7-ethyl-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet (TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharrna) BNP-1350 (BioNumerik) Rebeccamycin analogue CKD-602 (Chong Kun Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin Losoxantrone Daunorubicin (Daunomycin) Bleomycin sulfate Epirubicin (Blenoxan) Therarubicin Bleomycinic acid Idarubicin Bleomycin A Rubidazon Bleomycin B Plicamycinp Mitomycin C Porfiromycin MEN-10755 (Menarini) Cyanomorpholinodoxorubicin GPX-100 (Gem Mitoxantron (Novantron) Pharmaceuticals) Antimitotic active Paclitaxel SB 408075 compounds Docetaxel (GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell Therapeutics) Vincristine IDN 5109 (Bayer) Vinorelbine A 105972 (Abbott) Vindesine A 204197 (Abbott) Dolastatin 10 (NCI) LU 223651 (BASF) Rhizoxin (Fujisawa) D 24851 (ASTA Medica) Mivobulin (Warner-Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias) Synthase ZD-9331 (BTG) CoFactor ™ (BioKeys) inhibitors DNA antagonists Trabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (Baxter International) International) Apaziquone (Spectrum Albumin + 32P Pharmaceuticals) (isotope solutions) O6-benzylguanine Thymectacin (NewBiotics) (Paligent) Edotreotid (Novartis) Farnesyl transferas Arglabin (NuOncology Labs) Tipifarnib (Johnson & inhibitors Lonafarnib (Schering-Plough Johnson) BAY-43-9006 (Bayer) Perillyl alcohol (DOR BioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidar trihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex) Histone acetyl transferase Tacedinaline (Pfizer) Pivaloyloxymethyl butyrate inhibitors SAHA (Aton Pharma) (Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa) Metalloproteinase Neovastat (Aeterna CMT-3 (CollaGenex) inhibitors Laboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (British Biotech) Tezacitabine (Aventis) reductase Gallium maltolate (Titan) Didox (Molecules for inhibitors Triapin (Vion) Health) TNF-alpha Virulizin (Lorus Therapeutics Revimid (Celgene) agonists/ CDC-394 (Celgene) antagonists Endothelin-A receptor Atrasentan (Abbot) YM-598 (Yamanouchi) antagonists ZD-4054 (AstraZeneca) Retinoic acid Fenretinide (Johnson & Alitretinoin (Ligand) receptor agonists Johnson) LGD-1550 (ligand) Immunomodulators Interferon Dexosome therapy (Anosys Oncophage (Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology) Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine (Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovax vaccines (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera (Vasogen) Melanoma vaccines (CTL Immuno) p21-RAS vaccine (GemVax) Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogens Methylprednisolone active compounds Ethynyloestradiol Prednisolone Chlorotrianisene Aminoglutethimide Idenestrol Leuprolide Hydroxyprogesterone Goserelin caproate Leuporelin Medroxyprogesterone Bicalutamide Testosterone Flutamide Testosterone propionate Octreotide Fluoxymesterone Nilutamide Methyltestosterone Mitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyoestradiol Tamoxifen (En_treMed) Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic Talaporfin (Light Sciences) Pd bacteriopheophorbide active compounds Theralux (Theratechnologies (Yeda) Motexafin-Gadolinium Lutetium texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide(Sugen/Pharmacia) CEP-701 (Cephalon) ZDI839 (AstraZeneca) CEP-751 (Cephalon) Erlotinib (Oncogene Science MLN518 (Millenium) Canertjnib (Pfizer) PKC412 (Novartis) Squalamine (Genaera) Phenoxodiol O SU5416 (Pharmacia) Trastuzumab (Genentech) SU6668 (Pharmacia) C225 (ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210 (Medarex) Vatalanib (Novartis) 2C4 (Genentech) PKI166 (Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmithKline) ABX-EGF (Abgenix) EKB-509 (Wyeth) IMC-1C11 (ImClone) EKB-569 (Wyeth) Various other SR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, active compounds Sanofi-Synthelabo) BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist, Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin (RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor, Ivy Tirapazamine (reducing Medical) agent, SRI International) P54 (COX-2 inhibitor, N-Acetylcysteine Phytopharm) (reducing agent, CapCell ™ (CYP450 Zambon) stimulant, Bavarian Nordic) R-Flurbiprofen (NF-kappaB GCS-IOO (gal3 antagonist, inhibitor, Encore) GlycoGenesys) 3CPA (NF-kappaB G17DT immunogen (gastrin inhibitor, Active Biotech) inhibitor, Aphton) Seocalcitol (vitamin D Efaproxiral (oxygenator, receptor agonist, Leo) Allos Therapeutics) 131-I-TM-601 (DNA PI-88 (heparanase inhibitor, antagonist, Progen) TransMolecular) Tesmilifen (histamine Eflornithin (ODC inhibitor, antagonist, YM ILEX Oncology) BioSciences) Minodronic acid Histamine (histamine H2 (osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin (IMPDH inhibitor, Indisulam (p53 stimulant, Ribapharm) Eisai) Cilengitide (integrin Aplidin (PPT inhibitor, antagonist, PharmaMar) Merck KGaA) Rituximab (CD20 antibody, SR-31747 (IL-1 antagonist, Genentech) Sanofi-Synthelabo) Gemtuzumab (CD33 CCI-779 (mTOR kinase antibody, Wyeth Ayerst) inhibitor, Wyeth) PG2 (haematopoiesis Exisulind (PDE-V inhibitor, promoter, Pharmagenesis) Cell Pathways) Immunol ™ (triclosan CP-461 (PDE-V inhibitor, mouthwash, Endo) Cell Pathways) Triacetyluridine (uridine AG-2037 (GART inhibitor, prodrug, Wellstat) Pfizer) SN-4071 (sarcoma agent, WX-UK1 (plasminogen Signature BioScience) activator inhibitor, Wilex) TransMID-107 ™ PBI-1402 (PMN stimulant, (immunotoxin, KS ProMetic LifeSciences) Biomedix) Bortezomib (proteasome PCK-3145 (apoptosis promoter, inhibitor, Millennium) Procyon) SRL-172 (T-cell stimulant, Doranidazole (apoptosis SR Pharma) promoter, Pola) TLK-286 (glutathione-S CHS-828 (cytotoxic agent, transferase inhibitor, Telik) Leo) PT-100 (growth factor trans-Retinoic acid agonist, Point Therapeutics) (differentiator, NIH) Midostaurin (PKC inhibitor, MX6 (apoptosis promoter, Novartis) MAXIA) Bryostatin-1 (PKC stimulant, Apomine (apoptosis GPC Biotech) promoter, ILEX Oncology) CDA-II (apoptosis promoter, Urocidin (apoptosis Everlife) promoter, Bioniche) SDX-101 (apoptosis promoter, Ro-31-7453 (apoptosis Salmedix) promoter, La Roche) Ceflatonin (apoptosis promoter, Brostallicin (apoptosis ChemGenex) promoter, Pharmacia)

Even without further embodiments, it is assumed that a person skilled in the art will be able to use the above description in the broadest scope. The preferred embodiments should therefore merely be regarded as descriptive disclosure which is absolutely not limiting in any way.

The following examples are thus intended to explain the invention without limiting it. Unless indicated otherwise, percent data denote percent by weight. All temperatures are indicated in degrees Celsius. “Conventional work-up”: water is added if necessary, the pH is adjusted, if necessary, to values between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered and evaporated, and the product is purified by chromatography on silica gel and/or by crystallisation.

Rf values on silica gel; mass spectrometry: EI (electron impact ionisation): M⁺, FAB (fast atom bombardment): (M+H)⁺, THF (tetrahydrofuran), NMP (N-methlpyrrolidone), DMSO (dimethyl sulfoxide), EA (ethyl acetate), MeOH (methanol), TLC (thin-layer chromatography)

The following substances have been synthesised and characterised. However, the preparation and characterisation of the substances can also be carried out by other methods for the person skilled in the art.

EXAMPLE 1 Illustrative Compounds of the Formula I

TABLE 2 Compound CathD LC/MS No. Structure IC₅₀ nM (M + H) 1

300 617 2

190 505 3

140 461 4

110 626 5

3400 588 6

2600 592 7

3300 626 8

82 549 9

482 10

580 489 11

950 523 12

950 557 13

180 558 14

558 15

120 628 16

82 554 17

730 518 18

160 565 19

400 481 20

270 493 21

370 511 22

50 523 23

260 614 24

517 25

120 541 26

1400 489 27

1300 549 28

385 29

1000 543. 30

1900 476 31

476 32

110 543 33

170 441 34

660 455 35

280 455 36

230 523 37

130 549 38

100 535 39

170 455 40

290 427 41

469 42

230 455 43

31 461 44

24 489 45

240 407 46

26 489 47

760 533 48

490 49

1500 475 50

330 531 51

67 501 52

140 467 53

72 447 54

78 505 55

400 583 56

310 583 57

1900 509 58

890 481 59

520 60

17 529 61

74 537 62

1900 541 63

260 535 64

1800 485 65

1100 485 66

210 481 67

150 407 68

330 421 69

15 555 70

86 515 71

130 549 72

97 473 73

210 433 74

680 469 75

440 435 76

482 77

448 78

700 535 79

470 523 80

98 529 81

180 447 82

900 439 83

130 519 84

420 519 85

530 445 86

320 525 87

525 88

2400 483 89

1100 457 90

1300 487 91

1700 489 92

1800 463 93

57 543 94

270 513 95

940 449 96

490 495 97

2000 471 98

140 475 99

8.6 607 100

570 415 101

230 483 102

250 515 103

59 431 104

440 519 105

1300 489 106

140 413 107

440 501 108

110 549 109

55 526 110

90 614 111

380 377 112

160 459 113

240 431 114

110 499 115

2300 475 116

590 367 117

310 417 118

560 393 119

455 120

1300 481 121

1800 505 122

1900 475 123

980 493 124

2000 469 125

2700 411 126

1500 505 127

397 128

1700 543 129

578 130

2200 559 131

347 132

445 133

460 134

441 135

1900 407 136

333 137

441 138

446 139

427 140

210 568 141

58 535 142

200 519 143

280 535 144

130 554 145

130 510 146

120 475 147

360 524 148

659 149

2000 625 150

480 559 151

620 152

1600 590 153

590 154

390 535 155

240 523 156

48 447 157

46 529 158

533 159

960 445 160

620 527 161

2100 521 162

49 560 163

400 405 164

270 520 165

445 166

525 167

525 168

487 169

489 170

463 171

491 172

485 173

451 174

475 175

488 176

516 177

522 178

523 179

529 180

489 181

517 182

477 183

517 184

447 185

489 186

476 187

499 188

431 189

459 190

459 191

419 192

260 407 193

420 407 194

650 449 195

450 449 196

11 467 197

450 467 198

260 497 199

280 497 200

370 509 201

72 557 202

220 489 203

110 447 204

1200 535 205

610 523 206

447 207

110 529 208

11 507 209

320 507 210

210 537 211

260 537 212

92 549 213

230 511 214

170 435 215

63 517 216

360 511 217

230 435 218

120 516 219

760 471 220

1100 395 221

190 477 222

41 535 223

91 453 224

449 225

367 226

140 475 227

370 551 228

250 572 229

43 496 230

42 578 231

1600 549 232

770 473 233

450 555 234

250 548 235

230 466 236

970 541 237

476 238

> 394 239

541 240

1300 565 241

430 553 242

120 477 243

66 559 244

1500 511 245

900 499 246

340 423 247

200 505 248

120 445 249

410 405 250

498 251

422 252

504 253

220 549 254

460 509 255

280 567 256

440 527 257

280 565 258

530 525 259

240 609 260

320 593 261

57 523 262

310 577 263

230 561 264

84 555 265

530 583 266

620 543 267

290 585 268

200 585 269

240 588 270

140 628 271

380 571 272

44 549 273

510 509 274

110 421 275

51 504 276

81 567 277

690 527 278

74 616 279

520 280

476 281

13 560 282

1400 478 283

110 548 284

35 517 285

80 435 286

61 551 287

56 494 288

20 562 289

90 539 290

470 499 291

350 533 292

120 563 293

390 523 294

24 585 295

230 470 296

100 465 297

240 525 298

48 535 299

230 559 300

780 557 301

52 537 302

2000 555 303

490 561 304

2400 521 305

830 542 306

93 548 307

440 508 308

525 309

700 559 310

47 565 311

89 565 312

380 525 313

530 559 314

200 524 315

45 565 316

100 561 317

320 521 318

400 555 319

41 561 320

230 521 321

240 555 322

49 522 323

67 564 324

220 524 325

290 558 326

110 487 327

47 497 328

170 583 329

550 543 330

630 577 331

550 507 332

100 517 333

42 537 334

130 517 335

470 537 336

550 561 337

88 567 338

280 527 339

45 563 340

49 531 341

13 581 342

340 632 343

525 344

514 345

473 346

632 347

537 348

658 349

465 350

465

TABLE 3 The following compounds are also in accordance with the invention, where the numbering of the respective compound corresponds to the corresponding structure having the same numbering from Table 2, 1. (R)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 2. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methoxy- benzyl)-3-phenylpropionamide, 3. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(1-ethylpropyl)propionamide trifluoroacetate, 4. (R)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion- amide, 5. (S)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-(4-methoxyphenyl)propion- amide, 6. (S)-3-(4-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion- amide, 7. (S)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propion- amide, 8. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(3,4- dimethoxyphenyl)ethyl]-3-phenylpropionamide, 9. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide, 10. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-phenethyl-3- phenylpropionamide, 11. (R)-N-[2-(4-chlorophenyl)ethyl]-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 12. (R)-N-[2-(2,4-dichlorophenyl)ethyl]-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 13. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide, 14. (S)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3- dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide, 15. (R)-N-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 16. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- sulfamoylbenzyl)propionamide, 17. (R)-N-(4-cyano-3-fluorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 18. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-(4-methoxyphenyl)propionamide, 19. (R)-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide trifluoroacetate, 20. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro- benzyl)-3-phenylpropionamide, 21. (R)-N-(3,4-difluorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 22. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 23. (R)-N-(2-bromo-4,5-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 24. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((1S,2R)-2- hydroxyindan-1-yl)-3-phenylpropionamide, 25. (R)-3-cyclohexyl-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 26. (R)-N-benzyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- methyl-3-phenylpropionamide, 27. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-methyl-3-phenylpropionamide, 28. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionamide, 29. (R)-N-(3,4-dichlorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 30. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- pyridin-4-ylmethylpropionamide, 31. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- pyridin-2-ylmethylpropionamide, 32. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide, 33. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isobutyl-3- phenylpropionamide, 34. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2,2- dimethylpropyl)-3-phenylpropionamide, 35. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methyl- butyl)-3-phenylpropionamide, 36. (R)-N-(4-tert-butylcyclohexyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 37. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2- methoxyethoxy)benzyl]-3-phenylpropionamide, 38. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2- hydroxyethoxy)benzyl]-3-phenylpropionamide, 39. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-ethyl- propyl)-3-phenylpropionamide, 40. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isopropyl-3- phenylpropionamide, 41. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-ethyl- butyl)-3-phenylpropionamide, 42. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-2- methylbutyl)-3-phenylpropionamide, 43. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-((S)-2-methylbutyl)propionamide, 44. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-methoxybenzyl amide, 45. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid isobutyl amide, 46. (2R,3R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanecarboxylic acid 4-fluoro-3-methoxybenzyl amide, 47. (R)-N-(2-benzo-1,3-dioxol-5-ylethyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 48. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(2- pyridin-4-ylethyl)propionamide, 49. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-hydroxypropionamide, 50. (R)-3-tert-butoxy-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 51. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3,4-dimethoxybenzyl amide, 52. (R)-N-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide, 53. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 54. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxy- benzyl)-3-phenylpropionamide, 55. (R)-3-(2-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 56. (R)-3-(4-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide, 57. 5-((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)furan-2-carboxylic acid methyl ester, 58. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- thiophen-2-ylmethylpropionamide, 59. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-ethoxy- pyridin-2-ylmethyl)-3-phenylpropionamide, 60. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 61. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-4-phenylbutyramide, 62. (1S,3S,4S)-4-((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionylamino)-3-hydroxycyclohexanecarboxylic acid methyl ester, 63. (R)-N-(3,5-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 64. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((R)-1- hydroxymethyl-3-methylbutyl)-3-phenylpropionamide, 65. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-1- hydroxymethyl-3-methylbutyl)-3-phenylpropionamide, 66. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methyl- cyclohexyl)-3-phenylpropionamide, 67. (2R,3R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanoic acid isobutyl amide, 68. R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((S)-2-methylbutyl) amide, 69. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[1-(4-fluoro-3-methoxyphenyl)cyclopropyl]propionamide, 70. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid [1-(4-fluoro-3-methoxyphenyl)cyclopropyl] amide, 71. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[1-(4-fluoro- 3-methoxyphenyl)cyclopropyl]-3-phenylpropionamide, 72. (R)-3,N-dicyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide, 73. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclohexyl amide, 74. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydropyran-4-yl)propionamide, 75. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (tetrahydropyran-4-yl) amide, 76. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-methyl- piperidin-4-yl)-3-phenylpropionamide, 77. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (1-methylpiperidin-4-yl) amide, 78. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 79. (R)-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 80. (R)-3-cyclohexyl-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 81. (R)-3-cyclohexyl-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 82. (R)-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 83. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)-1-(3- methoxyphenyl)ethyl]-3-phenylpropionamide, 84. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)-1-(3- methoxyphenyl)ethyl]-3-phenylpropionamide, 85. (S)-3-cyclohexyl-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 86. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(S)-1-(3-methoxyphenyl)ethyl]propionamide, 87. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(R)-1-(3-methoxyphenyl)ethyl]propionamide, 88. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydropyran-4-ylmethyl)propionamide, 89. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxy- propyl)-3-phenylpropionamide, 90. (S)-3-cyclohexyl-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 91. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-ylmethyl)propionamide, 92. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-methoxypropyl)propionamide, 93. (R)-3-cyclohexyl-2-{N′-[3-(3,4-dimethoxyphenyl)propionyl]- guanidino}-N-(4-fluoro-3-methoxybenzyl)propionamide, 94. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N- (4-fluoro-3-methoxybenzyl)propionamide, 95. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(4-methyl- pentanoyl)guanidino]propionamide, 96. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(indane-2- carbonyl)guanidino]propionamide, 97. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-dimethoxybenzyl amide, 98. (R)-3-cyclohexyl-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3- methoxybenzyl)propionamide, 99. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 100. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-[N′-(3-phenylpropionyl)- guanidino]propionamide, 101. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(3-phenyl- propionyl)guanidino]propionamide, 102. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-(N′-phenylacetyl- guanidino)propionamide, 103. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N- isobutylpropionamide, 104. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-N-(3,4- dimethoxybenzyl)-3-phenylpropionamide, 105. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-[N′-(3-phenylpropionyl)- guanidino]propionamide, 106. (R)-3-cyclohexyl-2-[N′-(indane-2-carbonyl)guanidino]-N-isobutyl- propionamide, 107. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(indane-2-carbonyl)guanidino]-3- phenylpropionamide, 108. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[3-(3,4-dimethoxyphenyl)- propionyl]guanidino}-3-phenylpropionamide, 109. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-isobutylpropionamide, 110. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-N- (3,4-dimethoxybenzyl)-3-phenylpropionamide, 111. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid isobutyl amide, 112. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-methoxybenzyl amide, 113. (R)-3-cyclohexyl-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-N- ((S)-2-methylbutyl)propionamide, 114. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-methoxy- phenyl)acetyl]guanidino}propionamide, 115. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-(N′-phenylacetyl- guanidino)propionamide, 116. (R)-3-cyclohexyl-N-isobutyl-2-[N′-(4-methylpentanoyl)guanidino]- propionamide, 117. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-(3-methoxyphenyl)acetyl]- guanidino}propionamide, 118. (R)-3-cyclohexyl-2-[N′-(2-cyclohexylacetyl)guanidino]-N-isobutyl- propionamide, 119. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(4-methylpentanoyl)guanidino]- 3-phenylpropionamide, 120. (R)-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(3,4-dimethoxybenzyl)- 3-phenylpropionamide, 121. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 122. (R)-N-(3-methoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 123. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 124. (R)-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide, 125. (R)-N-isobutyl-2-{N′-[2-(4-methoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 126. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(4-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 127. (R)-N-isobutyl-2-[N′-(2-phenoxyacetyl)guanidino]-3-phenylpropion- amide, 128. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(4-trifluoromethyl- phenyl)acetyl]guanidino}propionamide, 129. (R)-3-phenyl-N-(4-sulfamoylbenzyl)-2-{N′-[2-(4-trifluoromethoxy- phenyl)acetyl]guanidino}propionamide, 130. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(4-trifluoromethoxy- phenyl)acetyl]guanidino}propionamide, 131. (R)-N-isobutyl-2-[N′-(3-methylbutyryl)guanidino]-3-phenylpropion- amide, 132. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-[N′-(3-methylbutyryl)- guanidino]-3-phenylpropionamide, 133. (R)-2-[N′-(3-methylbutyryl)guanidino]-3-phenyl-N-(4-sulfamoyl- benzyl)propionamide, 134. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(3-methylbutyryl)guanidino]-3- phenylpropionamide, 135. (R)-4-methyl-2-[N′-(3-methylbutyryl)guanidino]-pentanoic acid 3,4- dimethoxybenzyl amide, 136. (R)-N-isobutyl-2-(N′-isobutyrylguanidino)-3-phenylpropionamide, 137. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N′-isobutyrylguanidino)-3- phenylpropionamide, 138. (R)-2-(N′-isobutyrylguanidino)-3-phenyl-N-(4-sulfamoylbenzyl)- propionamide, 139. (R)-N-(3,4-dimethoxybenzyl)-2-(N′-isobutyrylguanidino)-3-phenyl- propionamide, 140. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-methyl- sulfamoylbenzyl)-3-phenylpropionamide, 141. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 142. (R)-N-benzo-1,3-dioxol-5-ylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide, 143. (R)-N-(2,3-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 144. (R)-N-(3-bromobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 145. (R)-N-(3-chlorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 146. (R)-N-benzyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide, 147. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxy- phenyl)ethyl]-3-phenylpropionamide, 148. (S)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 149. (S)-3-(4-chlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 150. (R)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)- ethyl]-2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 151. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-(4-methoxy- phenyl)-2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide, 152. (R)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N′-[2-(3- phenoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 153. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N′-[2-(3- phenoxyphenyl)acetyl]guanidino}-3-phenylpropionamide, 154. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 155. (R)-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 156. (R)-3-cyclohexyl-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 157. (R)-3-cyclohexyl-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 158. (R)-2-[N′-(2-adamantan-1-ylacetyl)guanidino]-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide, 159. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-isobutyl- propionamide, 160. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide, 161. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide, 162. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-sulfamoylbenzyl)propionamide, 163. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclopropylmethyl amide, 164. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-sulfamoylbenzyl amide, 165. (R)-3-cyclohexyl-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 166. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(S)-1-(3-methoxyphenyl)ethyl]propionamide, 167. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[(R)-1-(3-methoxyphenyl)ethyl]propionamide, 168. (R)-3-cyclohexyl-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 169. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-ylmethyl)propionamide, 170. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-methoxypropyl)propionamide, 171. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydrothiopyran-4-yl)propionamide, 172. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N- (tetrahydrothiopyran-4-yl)propionamide, 173. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (tetrahydrothiopyran-4-yl) amide, 174. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(tetrahydropyran-4-yl)propionamide, 175. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(1-methylpiperidin-4-yl)propionamide, 176. (R)-N-(5-chlorothiophen-2-ylmethyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 177. (R)-N-(5-chlorothiophen-2-ylmethyl)-3-cyclohexyl-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 178. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-fluoro-4- methoxybenzyl)-3-phenylpropionamide, 179. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-fluoro-4-methoxybenzyl)propionamide, 180. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-fluoro-4-methoxybenzyl amide, 181. (R)-3-cyclohexyl-N-(3,4-difluorobenzyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide, 182. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3,4-difluorobenzyl amide, 183. (R)-N-(6-chloropyridin-3-ylmethyl)-3-cyclohexyl-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 184. (R)-N-((S)-sec-butyl)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 185. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(trans-4-hydroxycyclohexyl)propionamide, 186. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (6-chloropyridin-3-ylmethyl) amide, 187. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluorobenzyl)propionamide, 188. (R)-3-cyclohexyl-N-cyclopropyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 189. (R)-3-cyclohexyl-N-cyclopentyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 190. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluorobenzyl amide, 191. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclopentyl amide, 192. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((S)-sec-butyl) amide, 193. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid ((R)-sec-butyl) amide, 194. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (trans-4-hydroxycyclohexyl) amide, 195. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (cis-4-hydroxycyclohexyl) amide, 196. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (S)-indan-1-yl amide amide, 197. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (R)-indan-1-ylamide amide, 198. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (4-methoxyindan-2-yl) amide, 199. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid (5-methoxyindan-2-yl) amide, 200. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide, 201. (R)-3-cyclohexyl-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 202. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(cis-4-hydroxycyclohexyl)propionamide, 203. (R)-N-((R)-sec-butyl)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 204. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide, 205. (R)-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 206. (R)-3-cyclohexyl-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide, 207. (R)-3-cyclohexyl-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-methoxybenzyl)propionamide, 208. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(S)-indan-1-ylpropionamide)propionamide, 209. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(R)-indan-1-ylpropionamide, 210. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-methoxyindan-2-yl)propionamide, 211. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(5-methoxyindan-2-yl)propionamide, 212. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 213. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3-methoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 214. (R)-3-cyclohexyl-2-{N′-[2-(4-fluoro-3-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 215. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3- methoxyphenyl)acetyl]guanidino}propionamide, 216. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4-methoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide, 217. (R)-3-cyclohexyl-2-{N′-[2-(3-fluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 218. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide, 219. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-[N′-(2-tetrahydro- pyran-4-ylacetyl)guanidino]propionamide, 220. (R)-3-cyclohexyl-N-isobutyl-2-[N′-(2-tetrahydropyran-4-ylacetyl)- guanidino]propionamide, 221. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-tetrahydro- pyran-4-ylacetyl)guanidino]propionamide, 222. (R)-3-cyclohexyl-2-{N′-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-(4-fluoro-3-methoxybenzyl)propionamide, 223. (R)-3-cyclohexyl-2-{N′-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 224. (R)-3-cyclohexyl-2-[N′-(3,3-dimethylbutyryl)guanidino]-N-(4-fluoro- 3-methoxybenzyl)propionamide, 225. (R)-3-cyclohexyl-2-[N′-(3,3-dimethylbutyryl)guanidino]-N-isobutyl- propionamide. 226. (R)-3-cyclohexyl-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide, 227. (R)-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 228. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)-3-phenylpropionamide, (R)-2-{N′-[2-(2- bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutyl- propionamide, 229. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-isobutylpropionamide, 230. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 231. (S)-2-benzyl-4-{N′-[(R)-1-(4-fluoro-3-methoxybenzylcarbamoyl)-2- phenylethyl]guanidino}-4-oxobutyric acid methyl ester, 232. (S)-2-benzyl-4-[N′-((R)-2-cyclohexyl-1-isobutylcarbamoylethyl)- guanidino]-4-oxobutyric acid methyl ester, 233. (S)-2-benzyl-4-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid methyl ester, 234. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 235. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N- isobutylpropionamide, 236. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 237. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-((S)-5-oxo- pyrrolidin-2-yl)acetyl]guanidino}propionamide, 238. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-((S)-5-oxopyrrolidin-2-yl)- acetyl]guanidino}propionamide, 239. (S)-2-benzyl-4-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid, 240. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(2,3,4-trimethoxy- phenyl)acetyl]guanidino}propionamide, 241. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-{N′-[2-(2,3,4- trimethoxyphenyl)acetyl]guanidino}propionamide, 242. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-(2,3,4-trimethoxyphenyl)- acetyl]guanidino}propionamide, 243. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2,3,4- trimethoxyphenyl)acetyl]guanidino}propionamide, 244. (R)-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide, 245. (R)-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 246. (R)-3-cyclohexyl-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N- isobutylpropionamide, 247. (R)-3-cyclohexyl-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 248. (R)-N-cyclobutyl-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide, 249. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid cyclobutyl amide, 250. (R)-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, 251. (R)-3-cyclohexyl-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N- isobutylpropionamide, 252. (R)-3-cyclohexyl-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 253. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-trifluoromethylbenzyl)propionamide, 254. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-trifluoromethylbenzyl amide, 255. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-trifluoromethylbenzyl)propionamide, 256. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-trifluoromethylbenzyl amide, 257. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-trifluoromethoxybenzyl)propionamide, 258. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-trifluoromethoxybenzyl amide, 259. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N′-[2-(4- fluoro-3-trifluoromethylphenyl)acetyl]guanidino}propionamide, 260. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N′-[2-(4- fluoro-3-trifluoromethylphenyl)acetyl]guanidino}propionamide, 261. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2,4,6- trifluorophenyl)acetyl]guanidino}propionamide, 262. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N′-[2- (2,4,6-trifluorophenyl)acetyl]guanidino}propionamide, 263. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N′-[2- (2,4,6-trifluorophenyl)acetyl]guanidino}propionamide, 264. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3- trifluoromethylphenyl)acetyl]guanidino}propionamide, 265. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-fluoro-3-trifluoromethoxybenzyl)propionamide, 266. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-fluoro-3-trifluoromethoxybenzyl amide, 267. (R)-N-[(S)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2- {N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 268. (R)-N-[(R)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2- {N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 269. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-4- methylpentanecarboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide, 270. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3- cyclohexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 271. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4- trifluoromethoxyphenyl)acetyl]guanidino}propionamide, 272. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-(1H-tetrazol-5-yl)benzyl]propionamide, 273. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-(1H-tetrazol-5-yl)benzyl amide, 274. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N- isobutylpropionamide, 275. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 276. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-fluoro-4-(1H-tetrazol-5-yl)benzyl]propionamide, 277. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-fluoro-4-(1H-tetrazol-5-yl)benzyl amide, 278. (R)-2-{N′-[2-(2-bromo-4-trifluoromethylphenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 279. (R)-2-[N′-((2S,4R)-1-acetyl-4-methoxypyrrolidine-2-carbonyl)- guanidino]-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propion- amide, 280. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-piperidin-1- ylacetyl)guanidino]propionamide, 281. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-sulfamoylbenzyl)propionamide, 282. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-morpholin- 4-ylacetyl)guanidino]propionamide, 283. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4- sulfamoylphenyl)acetyl]guanidino}propionamide, 284. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide, 285. (R)-3-cyclohexyl-2-{N′-[2-(2-fluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide, 286. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl]acetyl}guanidino)propionamide, 287. (R)-2-{N′-[2-(3-cyanophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide, 288. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3- methanesulfonylaminophenyl)acetyl]guanidino}propionamide, 289. 4-[((R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionylamino)methyl]benzoic acid methyl ester, 290. 4-[((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester, 291. 4-[((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)methyl]benzoic acid methyl ester, 292. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propionamide, 293. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl amide, 294. 4-(2-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzylcarbamoyl)- ethyl]guanidino}-2-oxoethyl)-2-ethoxybenzoic acid ethyl ester, 295. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-pyridin-2-yl- acetyl)guanidino]propionamide, 296. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-isobutoxy- acetyl)guanidino]propionamide, 297. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-(1,2,3-thiadiazol-4-yl)benzyl amide, 298. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(3- sulfamoylbenzyl)propionamide, 299. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- (1,2,3-thiadiazol-4-yl)benzyl)propionamide, 300. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl]-3-phenylpropionamide, 301. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-tetrazol- 1-ylphenyl)acetyl]guanidino}propionamide, 302. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl- imidazol-1-yl)benzyl]-3-phenylpropionamide, 303. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(2-methylimidazol-1-yl)benzyl]propionamide, 304. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-(2-methylimidazol-1-yl)benzyl amide, 305. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- (1,2,4-triazol-1-yl)benzyl)propionamide, 306. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-1,2,4-triazol-1-ylbenzyl)propionamide, 307. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(1,2,4-triazol-1-yl)benzyl amide, 308. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 4-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 309. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-(5- hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 310. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 311. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 312. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 313. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5- hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 314. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-[4- (1H-tetrazol-5-yl)benzyl]propionamide, 315. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(4-1,2,3-thiadiazol-4-ylbenzyl)propionamide, 316. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(2-methyl-2H-pyrazol-3-yl)benzyl]propionamide, 317. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(2-methyl-2H-pyrazol-3-yl)benzyl amide, 318. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl- 2H-pyrazol-3-yl)benzyl]-3-phenylpropionamide, 319. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[3-(1-methyl-1H-pyrazol-3-yl)benzyl]propionamide, 320. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-(1-methyl-1H-pyrazol-3-yl)benzyl amide, 321. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(1-methyl- 1H-pyrazol-3-yl)benzyl]-3-phenylpropionamide, 322. (R)-2-{N′-[2-(4-chloro-2-fluorophenyl)acetyl]guanidino}-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 323. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-(3-thiazol-2-ylbenzyl)propionamide, 324. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 3-thiazol-2-ylbenzyl amide, 325. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- thiazol-2-ylbenzyl)propionamide, 326. (R)-2-[N′-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3- cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide, 327. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide, 328. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide, 329. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide, 330. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3- (5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide, 331. (R)-2-[N′-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3- cyclohexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide, 332. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- [3-(1H-tetrazol-5-yl)benzyl]propionamide, 333. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[4-(2H- tetrazol-5-yl)phenyl]acetyl}guanidino)propionamide, 334. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-propyl- cyclohexyl)acetyl]guanidino}propionamide, 335. (R)-3-cyclohexyl-2-{N′-[2-(4-propylcyclohexyl)acetyl]guanidino}-N- [3-(1H-tetrazol-5-yl)benzyl]propionamide, 336. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3- (2H-tetrazol-5-yl)benzyl]-3-phenylpropionamide, 337. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-[4-fluoro-3-(2H-tetrazol-5-yl)benzyl]propionamide, 338. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoic acid 4-fluoro-3-(2H-tetrazol-5-yl)benzyl amide, 339. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-{(S)-1-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 340. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N- {(S)-1-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 341. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- N-{(S)-1-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide, 342. (R)-N-[4-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N′-[2- (3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 343. 4-[((R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionylamino)methyl]benzoic acid, 344. 3-[((R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl- propionylamino)methyl]benzoic acid methyl ester, 345. 3-[((R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester, 346. (R)-N-[3-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N′-[2- (3,4-dimethoxyphenyl)acetyl]guanidino}propionamide, 347. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[3-(2H- tetrazol-5-yl)phenyl]acetyl}guanidino)propionamide, 348. (R)-N-{1-[4-(bistrifluoromethylamino)phenyl]cyclopropyl}-3- cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propion- amide, 349. (R)-3-cyclohexyl-N-((R)-2,3-dihydroxypropyl)-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, 350. (R)-3-cyclohexyl-N-((S)-2,3-dihydroxypropyl)-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide, and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

For the avoidance of any doubt, the compound according to the invention is unambiguously defined by the depiction of the chemical structure in all cases where the chemical name of the compound and the depiction of the chemical structure of the compound for a compound according to the invention incorrectly do not agree.

The mass signals were determined on an Agilent 1200 instrument: Chromolith Speed Rod RP 18e 50-4.6 mm LCMS; polar. m, 2.4 ml/min, 220 nm, buffer A 0.05% of HCOOH/H2O, buffer B 0.04% of HCOOH/ACN, 0.0-2.8 min 4%-100% of buffer B; 2.8-3.3 min 100% of buffer B 3.3-3.4 min 100%-4% of buffer B

The retention times were determined on a Merck-Hitachi LaChrom instrument:

Chromolith Speed Rod RP18e-100-4.6 HPLC; 5 min 4 ml 215 nm; 4 ml/min, 215 nm, buffer A 0.05% of TFA/H2O, buffer B 0.04% of TFA/ACN, 0.0-0.2 min 5% of buffer B; 0.2-5.0 min 5%-100% of buffer B; 5.0-5.5 min 99%-5% of buffer B

EXAMPLE 2 Preparation of (R)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide trifluoroacetate (compound No. 1)

197.4 μl of 4-methylmorpholine were added to the solution of 500 mg (1.5 mmol) of (R)-2-tert-butoxycarbonylamino-3-(2,4-dichlorophenyl)propionic acid in 10 ml of tetrahydrofuran under nitrogen, and the mixture was cooled to −50° C. After addition of 194.6 μl (1.5 mmol) of isobutyl chloroformate, the reaction solution was stirred at −50° C. for 15 min, 248.7 (1.5 mmol) of 2-(3,4-dimethoxyphenyl)ethylamine were then added, the mixture was subsequently stirred at −40° C. for a further 30 min and at room temperature for two hours. The reaction mixture was then evaporated in vacuo, the residue was taken up in 10 ml of 5% sodium hydrogencarbonate solution, and the aqueous mixture was extracted three times with 10 ml of ethyl acetate each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gave 655 mg (88% yield) of tert-buty {(R)-2-(2,4-dichlorophenyl)-1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]ethyl}carbamate as colourless crystals. LC/MS (M+Na):520.

655 mg (1.32 mmol) of tert-butyl {(R)-2-(2,4-dichlorophenyl)-1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]ethyl}carbamate (1a)) were dissolved in 15 ml of dioxane, and 15 ml of 4N HCl/dioxane solution were added. Reaction mixture was subsequently stirred overnight at room temperature, then evaporated to dryness, and the residue was dried in vacuo at 60° C. for five hours, giving 571 mg (100%) of (R)-2-amino-3-(2,4-dichlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide hydrochloride as pale-yellow solid. LC/MS (M+H) 397. ¹H NMR (500 MHz, DMSO-d⁶) δ 8.53 (broad s, 4H; NH), 7.61 (d, J=2.0, 1H), 7.39 (dd, J=8.3, 2.0, 1 H), 7.34 (d, J=8.3, 1 H), 6.83 (d, J=8.2, 1 H), 6.78 (d, J=1.8, 1H), 6.63 (dd, J=8.1, 1.7, 1H), 3.94 (broad s, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.32-3.26 (m, 1H), 3.18 (dq, J=12.5, 6.4, 2H), 3.09 (dd, J=13.8, 8.4, 1 H), 2.61-2.51 (m, 2H).

c) 2-(3,4-Dimethoxyphenyl)-N-(iminopyrazol-1-ylmethyl)acetamide

1.067 ml (1.2 mmol)) of ethyl chloroformate were added to the solution of 2 g (10.2 mmol) of 3,4-dimethoxyphenylacetic acid and 2.24 ml of 4-methylmorpholine in 50 ml of dichloromethane with ice-cooling and under an N₂ atmosphere, The reaction mixture was subsequently stirred with ice-cooling for one hour, 1.64 g (11.2 mmol) of pyrazole-1-carboxamidine hydrochloride were then added, and stirring was continued at room temperature for fifteen hours. The reaction solution was then washed with 10 ml of 5% sodium hydrogencarbonate solution and 10 ml of water and dried over sodium sulfate. After the desiccant had been filtered off and the solvent had been stripped off, the product was purified by column chromatography. Yield 1.85 g (62.1%) LC/MS (M+H) 289. ¹H NMR (400 MHz, DMSO-d⁶) δ 9.30 (broad s, 2H), 8.46 (d, J=2.6, 1 H), 7.91 (d, J=1.6, 1H), 6.93 (d, J=1.7, 1H), 6.87 (d, J=8.2, 1H), 6.81 (dd, J=8.2, 1.7, 1H), 6.58 (dd, J=2.6, 1.6, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.62 (s, 2H).

100 mg (0.35 mmol) of 2-(3,4-dimethoxyphenyl)-N-(iminopyrazol-1-yl-methyl)acetamide (1c)) and 150.45 mg (0.35 mmol) of (R)-2-amino-3-(2,4-dichlorophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide hydrochloride (1 b)) are suspended in 2 ml of tetrahydrofuran. After addition of 58 μl of triethylamine, the suspension is heated at 90° C. for 2 hours and then cooled to room temperature. The reaction mixture is subsequently evaporated to dryness, and the residue is purified by column chromatography (RP-HPLC select B; 0.1% solution of trifluoroacetic acid in acetonitrile/water), giving 44 mg (16.5%) of the title compound in the form of the trifluoroacetate salt as white amorphous solid. LC/MS (M+H) 617. ¹H NMR (500 MHz, DMSO-d⁶) δ 11.32 (s, 1H), 8.99 (d, J=8.3, 1H), 8.88 (broad s, 2H), 8.32 (t, J=5.2, 1H), 7.54 (s, 1H), 7.29 (dd, J=8.3, 2.0, 1H), 7.14 (d, J=8.3, 1H), 6.93 (d, J=8.2, 1 H), 6.89 (d, J=1.5, 1 H), 6.84 (d, J=8.2, 1 H), 6.79 (dd, J=8.0, 1.6, 2H), 6.67 (dd, J=8.1, 1.6, 1H), 4.62 (dd, J=13.0, 5.5, 1H), 3.75 (s, 6H), 3.73 (s, 3H), 3.70 (s, 3H), 3.67 (s, 2H), 3.40-3.27 (m, 3H), 3.04 (dd, J=14.3, 6.4, 1 H), 2.76-2.56 (m, 2H).

Compounds Nos. 4-14 were prepared analogously to the process from Example 2.

EXAMPLE 3 Preparation of (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]-guanidino}-N-(4-methoxybenzyl)-3-phenylpropionamide trifluoroacetate a) tert-Butyl[1-[2-(3,4-dimethoxyphenyl)acetylamino]-1-pyrazol-1-ylmeth-(Z)-ylidene]carbamate

1.17 g (29.38 mmol; 60% suspension in paraffin oil) of sodium hydride are added to the solution of 2.42 g (8.4 mmol) of 2-(3,4-dimethoxyphenyl)-N-(iminopyrazol-1-ylmethyl)acetamide (1c)) in 50 ml of tetrahydrofuran and 2 ml of dimethylformamide with ice-cooling and under a nitrogen atmosphere, and the mixture is stirred for 20 min. After addition of 11 g (50.36 mmol) of di-tert-butyl dicarbonate, the reaction mixture is stirred at room temperature for 48 hours, then evaporated to dryness, the residue is taken up in 10 ml of 5% sodium hydrogencarbonate solution, and the aqueous mixture is extracted three times with 10 ml of ethyl acetate each time. After the combined organic extracts have been dried over sodium sulfate and the solvent has been stripped off, the product is purified by column chromatography on silica gel (ethyl acetate/n-heptane), giving 1.86 g (52.5%) of tert-butyl[1-[2-(3,4-dimethoxyphenyl)acetylamino]-1-pyrazol-1-ylmeth-(Z)-ylidene]-carbamate as pale-yellow oil which gradually crystallises. LC/MS: 411 (M+Na). ¹H NMR (400 MHz, DMSO-d⁶) δ 11.24 (s, 1H), 8.40 (s, 1H), 7.92 (s, 1H), 6.95 (s, 1H), 6.90 (d, J=8.2, 1 H), 6.84 (d, J=8.2, 1 H), 6.63 (s, 1H), 3.76 (s, 3H), 3.75 (s, 2H), 3.74 (s, 3H), 1.38 (s, 9H).

50 mg of N-ethyldiisopropylamine and 54.5 mg (0.17 mmol) of (R)-2-amino-N-(4-methoxybenzyl)-3-phenylpropionamide hydrochloride (prepared analogously to 1 b)) are added to the solution of 60 mg (0.15 mmol) of tert-butyl[1-[2-(3,4-dimethoxyphenyl)acetylamino]-1-pyrazol-1-ylmeth-(Z)-ylidene]carbamate (2a)) in 3 ml of tetrahydrofuran, the reaction mixture obtained in this way is stirred at room temperature for 18 hours and then evaporated to dryness. The residue is then dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid is added to the solution, the reaction solution is stirred at room temperature for 15 hours and then evaporated in vacuo. After trituration of the residue with methanol, the product is filtered off with suction and dried at 60° C. in a vacuum drying cabinet for three hours, giving 42 mg (53.8%) the title compound as white powder. LC/MS (M+H) 505. ¹H NMR (500 MHz, DMSO-d⁶) δ 11.31 (s, 1H), 8.94 (d, J=8.0, 1H), 8.84 (s, 2H), 8.69 (t, J=4.9, 1H), 7.28-7.19 (m, 3H), 7.17-7.11 (m, 2H), 7.10 (d, J=8.4, 2H), 6.92 (d, J=8.2, 1H), 6.89 (s, 1H), 6.86 (d, J=8.6, 2H), 6.79 (d, J=8.1, 1H), 4.65 (dd, J=12.8, 6.4, 1H), 4.22 (qd, J=14.7, 5.7, 2H), 3.74 (s, 6H), 3.73 (s, 3H), 3.68 (s, 2H), 3.16 (dd, J=13.9, 5.3, 1H), 3.03 (dd, J=13.9, 6.8, 1H).

Compounds Nos. 15-67 were prepared analogously to the process from Example 3.

EXAMPLE 4 (R)-3-Cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]-guanidino}-N-(1-ethylpropyl)propionamide a) BOC-guanidine

BOC-guanidine was synthesised in accordance with Ando et al., Tetrahedron (2010), 66(32), 6224-6237: 22.93 g (0.24 mol) of guanidinium chloride are added to the solution of 19.2 g (0.48 mol) of sodium hydroxide pellets in 50 ml of water at 0° C. The solution is left to stir for 10 min., a solution of 13.1 g (60 mmol) of di-tert-butyl dicarbonate in 150 ml of acetone is then added in one portion at 0° C., and the reaction mixture is then left to stir at room temperature for 15 hours. The acetone is subsequently stripped off in vacuo, and the aqueous mixture is extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with 50 ml of saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off, the residue is recrystallised from ethyl acetate/n-heptane, giving 8.7 g (91%) of BOC-guanidine as white crystals. EI−MS (M+): 159.

b) (3,4-Dimethoxyphenyl)acetyl chloride

5 μl of dimethylformamide and then, dropwise, 10.93 ml (127.42 mmol) of oxalyl chloride are added to the solution of 5.00 g (25.48 mmol) of 3,4-dimethoxyphenylacetic acid in 100 ml of dichloromethane with ice-cooling and stirring, and, after removal of the cooling, the mixture is stirred at room temperature for two hours. The reaction mixture is subsequently evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, the toluene is stripped off again, the residue is taken up again in 10 ml of toluene, and the toluene is stripped off again. The residue was finally taken up twice in 10 ml of diethyl ether each time, and the diethyl ether was stripped off again, giving 5.5 g (96%) of (3,4-dimethoxyphenyl)acetyl chloride, which is reacted further without additional purification.

c) N-[2-(3,4-Dimethoxyphenyl)acetyl]-N′-(tert-butyloxycarbonyl)guanidine

8.72 ml of N-ethyldiisopropylamine are added to the solution of 4.08 g (25.62 mmol) of BOC-guanidine (3a)) in 400 ml of dichloromethane, a solution of 5.50 g (25.62 mmol) of (3,4-dimethoxyphenyl)acetyl chloride (3b)) in 70 ml of dichloromethane is then slowly added dropwise under nitrogen at −10° C., the mixture is then left to stir with ice-cooling for one hour, and finally warmed to room temperature over the course of two hours. The reaction solution is then washed with 20 ml each of 5% sodium hydrogencarbonate solution and saturated sodium chloride solution and then dried over sodium sulfate. After the desiccant has been filtered off and the solvent has been stripped off, the product is purified by column chromatography on silica gel (ethyl acetate/n-heptane), giving 7.1 g (82.5%) of N-[2-(3,4-dimethoxyphenyl)acetyl]-N′-(tert-butyloxycarbonyl)-guanidine as yellow oil. LC/MS (M+H−BOC) 238.

d) tert-Butyl {[2-(3,4-dimethoxyphenyl)acetylamino]-[(Z)-trifluoromethanesulfonylimino]methyl}carbamate

(2010), 66(32), 6224-6237

Analogously to the literature (Feichtinger et al., J. Org. Chem., (1998), 63, 8432-8439), 5.1 g (15.12 mmol) of N-[2-(3,4-dimethoxyphenyl)acetyl]-N′-(tert-butyloxycarbonyl)guanidine (3c)); were dissolved in 50 ml of dichloromethane under an N₂ atmosphere. 5.24 ml of triethylamine were added to this solution, and the mixture was cooled to −78° C. 5.5 ml (33.26 mmol) of trifluoromethanesulfonic anhydride dissolved in 10 ml of dichloromethane were added dropwise to this solution at such a rate that the temperature did not rise above −65° C. The reaction mixture was then left to stir at −70° C. for a further 30 min. and then allowed to come to room temperature overnight. Reaction solution was then washed with 10 ml each of 1N sodium hydrogensulfate solution and water, dried over sodium sulfate, filtered and evaporated. The product was purified by column chromatography on silica gel (ethyl acetate/n-heptane), giving 4.4 g (58.1%) of tert-butyl {[2-(3,4-dimethoxyphenyl)acetylamino]-[(Z)-trifluoromethanesulfonylimino]methyl}carbamate LC/MS (M+H−BOC) 370.

35.43 μl of triethylamine were added to the solution of 60 mg (0.13 mmol) of tert-butyl {[2-(3,4-dimethoxyphenyl)acetylamino]-[(Z)-trifluoromethanesulfonylimino]methyl}carbamate (3d)) and 35.4 mg (0.13 mmol) of (R)-2-amino-3-cyclohexyl-N-(1-ethylpropyl)propionamide hydrochloride (prepared from (R)-2-tert-butoxycarbonylamino-3-cyclohexylpropionic acid and 1-ethyl-propylamine analogously to Example 1 b)) in 2 ml of dichloromethane, and the reaction mixture was stirred at room temperature for 18 hours. 1 ml of trifluoroacetic acid was subsequently added to the reaction mixture, the mixture was stirred at room temperature for a further two hours, then evaporated to dryness in vacuo, and the product was purified by column chromatography (RP-HPLC select B; 0.1% solution of trifluoroacetic acid in acetonitrile/water), giving 21 mg (28.4%) of the title compound as amorphous white powder. LC/MS (M+H) 461. ¹H NMR (500 MHz, DMSO-d⁶) δ 11.08 (s, 1H), 8.89 (d, J=7.9, 1 H), 8.80 (broad s, 2H), 6.92 (d, J=8.2, 1 H), 6.90 (d, J=1.6, 1 H), 6.81 (dd, J=8.2, 1.5, 1 H), 1.74-1.53 (m, 6H), 1.53-1.41 (m, 2H), 1.34 (dt, J=13.5, 7.5, 2H), 1.25 (m, 2H), 1.20-1.06 (m, 3H), 1.00-0.84 (m, 2H), 0.81 (td, J=7.4, 4.0, 6H).

Compounds Nos. 68-350 were prepared analogously to the process from Example 4.

Abbreviations

DCM=dichloromethane

DMA=dimethylacetamide

DMF=dimethylformamide

EA=ethyl acetate

MTBE=methyl tert-butyl ether

PE=petroleum ether

RT=room temperature

TFA=trifluoroacetic acid

EXAMPLE 5 In-Vitro Fluorescence Assay for the Identification of Cathepsin D Inhibitors

In order to identify modulators of cathepsin D activity, a continuous enzymatic test was carried out with a synthetic peptide which carries a fluorescent group (MCA=(7-methoxycoumarin-4-yl)acetyl) which is quenched by energy transfer from a Dpn (2,4 dinitrophenyl) group on the same molecule, in Greiner 384-well nb microtitre plates. Cleavage of the peptidic substrate by cathepsin D causes an increase in the fluorescence intensity. In order to determine the efficacy of substances, the time-dependent increase in the fluorescence intensity in the presence of the substance was compared with the time-dependent increase in fluorescence in the absence of substances. The reference substance used was pepstatin A (Sigma-Aldrich). The substrate used was MCA-GKPILFFRLK(Dnp)d-R—NH₂ (Enzo Life Sciences, Lörrach). The enzyme employed was cathepsin D isolated from the human liver (Sigma-Aldrich) in a final concentration of 1.4 nM. The test was carried out in 100 mM sodium acetate buffer, 1.25% (v/v) of DMSO, 0.25% (w/v) of Chaps, pH 5.5. 2 μl of each substance solution with serially diluted substance concentration were added to in each case 4 μl of cathepsin D solution and incubated at room temperature for 10 min. The reaction was started by addition of 2 μl of substrate solution (final concentration 5 μM). After carrying out a starting-point fluorescence measurement (excitation wavelength 340 nm/emission wavelength 450 nm) using an Envision multilabel reader (Perkin Elmer), the reaction was incubated at room temperature for 60 min. The amount of peptide fragment cleaved off during the reaction time was subsequently measured by determination of the increase in the fluorescence intensity at 450 nm (excitation wavelength 340 nm).

The IC₅₀ values of the compounds according to the invention are shown in Table 2 from Example 1.

EXAMPLE 6 Cartilage Explant Assay

In order to investigate the effect of potential cathepsin D inhibitors on cartilage degradation, a pH-induced model based on bovine explants is used. The pH of the medium in which the explants are cultivated is matched here to the pathophysiological pH of an arthrotic knee. This pH is pH 5.5. In this ex vivo model, potential cathepsin D inhibitors are subsequently investigated for their action with respect to stopping of the cartilage degradation process. If the cartilage is destroyed, glycosaminoglycans (GAGs) are released into the cell culture supernatant. The amount of GAGs liberated can be determined quantitatively with the aid of DMMB (dimethylmethylene blue hydrochloride). If sulfated GAGs are detected using dimethylmethylene blue hydrochloride, the decrease in the absorption at 633 nm is utilised. Since work can also be carried out at very low GAG concentrations, a dye/GAG complex does not precipitate out even after extended incubation of DMMB with GAG, which sometimes happens after only a short time in other measurement methods. In order to determine the concentration, a calibration line is also recorded using chondroitin sulfate. The GAG values can be used to calculate an IC₅₀ value, i.e. a concentration at which a substance exhibits 50% of its action.

Solutions:

Incubation Medium, pH 7.4:

DMEM without FBS, addition of 1% of Pen/Strep and 30 μg/ml of ascorbic acid, the medium is not stored.

Incubation Medium, pH 5.5:

DMEM without FBS, the pH is adjusted by addition of MES and monitored using a pH meter, addition of 1% of Pen/Strep and 30 μg/ml of ascorbic acid.

Solutions for the GAG Measurement:

DMMB colouring solution (V=500 ml):

Dissolve 8 mg of DMMB (dimethylmethylene blue) in 2.5 ml of ethanol+1 g of sodium formate+1 ml of formic acid, make up to 500 ml with bidistilled water.

Incubation Medium: FBS (Medium without FBS)

Chondroitin Sulfate Solutions (Standard Curve)

Preparation of standard solutions with the following concentrations: 50 μg/ml; 25 μg/ml; 12.5 μg/ml; 6.25 μg/ml; 3.125 μg/ml; 1.56 μg/ml; 0.78 μg/ml and a blank control of the medium. The preparation of the standard solution is carried out in the medium with which the experiment was also carried out.

1.) Procedure: pH-Induced Cartilage Degradation of Bovine Explants

The bovine explants are firstly prepared. The induction of the cartilage degradation is carried out in 96-multiwell plates. One explant is cultivated per well. In each case, 200 μl of DMEM (incubation medium pH 5.5) without FBS+30 μg/ml of ascorbic acid are added. Thus negative control, explants (n=4) are incubated at pH 7.4 (without FBS). This control is not included in the calculation of the data, but instead ensures that the pH change has the desired effect on the liberation of GAG. At this point, the substances to be tested are added. No pre-incubation of the explants is carried out. The explants are cultivated with the corresponding substances for 3 days in the incubator at 37° C. and 7.5% CO₂.

2.) Incubation Procedure

In order to investigate the effect of cathepsin D inhibitors on the liberation of GAG (glycosaminoglycan), the substances are employed in the desired concentration and cultivated for 3 days. The compounds to be tested are tested in a first experiment in a concentration of 1 μM and 1% of DMSO. Substances which have an effect of >50% on the liberation of GAG (this corresponds to <50% of the control in the Assay Explorer) are tested in the next experiment at 100 nM and 1% of DMSO. Substances which have an effect of >50% on the liberation of GAG under these conditions (this corresponds to <50% of the control in the Assay Explorer) are tested in a concentration/effect relationship. The compounds here are investigated in the following concentrations: 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM.

The positive control used is pepstatin A with a concentration of 0.01 μM.

The assay window is defined by the control (pH 5.5), defined as 0% effect, and the control pH 5.5+0.01 μM pepstatin A, defined as 100% effect. After incubation for 3 days, the cell culture supernatants are collected and stored at −20° C. or measured directly. The amount of liberated GAG is measured photometrically.

The effect (1 value) of the respective substance in % based on the positive control (pH 5.5+0.01 μM pepstatin A) and the negative control (pH 5.5) is reported for concentrations of 1 μM and 100 nM. The value represents the average of 4 replicants. In the determination of a concentration/effect relationship, an IC₅₀ value is reported to the database (Assay Explorer).

4.) Measurement

The cell culture supernatants (200 μl) are either measured directly or stored at −20° C. In order to ensure an accurate determination of the concentration (μg/ml of GAG in the supernatant) of GAG, the measurement values must be located in the linear region of the standard curve. In order to ensure this, various dilutions are routinely introduced (1/5, 1/10, 1/20, 1/40). The dilutions are prepared with medium and introduced automatically (Hamilton) into a 384-well plate (15 μl). 60 μl of DMMB solution are likewise added automatically (or using a multichannel pipette). A rapid colour reaction occurs, which is subsequently measured at 633 nm using a plate reader (for example Envision).

Depending on the amount of sample present, at least one double determination is carried out.

The data are provided by the MTP reader as csv or xls files and stored as raw data based on this format (xls) or used for the calculation of the percentage effect of the particular compound.

5.) Quality Controls

As control for the induction of the pH-induced cartilage degradation, 4 explants are incubated at pH 7.4. This corresponds to the physiological pH of the cartilage, and no effect on the liberation of GAG is thus expected here. These GAG values (μg/ml of supernatant) are thus always significantly lower than the GAG values for incucation at pH 5.5.

A further control, which both serves for checking of the experiment, but is also important for the definition of the assay window, is the pepstatin control (pH 5.5+0.01 μM pepstatin A). This substance non-specifically blocks the activity of most proteases and thus determines the maximum possible effect of a compound.

6.) Results

All compounds measured exhibited an IC₅₀ value of 10⁻⁸ to 10⁻¹⁰ M in the GAG assay.

(1) Klompmakers, A. & Hendriks, T. (1986) Anal. Biochem. 153, 80-84, Spectrophotometric Determination of Sulfated Glycosaminoglycans.

(2) Groves, P. J. et al. (1997) Anal. Biochem. 245, 247-248 Polyvinyl alcohol-stabilised binding of sulfated GAGs to dimethylmethylene blue.

EXAMPLE 7 Investigation of Anti-Hyperalgesic Effect in Animals

In order to induce an inflammation reaction, a carrageenan solution (CAR, 1%, 50 μl) was injected intra-articularly on one side into a rat knee joint. The uninjected side was used for control purposes. Six animals per group were used. The threshold was determined by means of a micrometer screw (medial-lateral on the knee joint), and the thermal hyperalgesia was determined by means of a directed infrared light source by the Hargreaves method (Hargreaves et al., 1988) on the sole of the foot. Since the site of inflammation (knee joint) is different from the site of measurement (paw sole), use is made here of the term secondary thermal hyperalgesia, the mechanism of which is of importance for the discovery of effective analgesics.

Experimental description of thermal hyperalgesia (Hargreaves test): the experimental animal is placed in a plastic chamber on a quartz sheet. Before testing, the experimental animal is firstly given about 5-15 minutes time to familiarise itself with the environment. As soon as the experimental animal no longer moves so frequently after the familiarisation phase (end of the exploration phase), the infrared light source, whose focus is in the plane of the glass bottom, is positioned directly beneath the rear paw to be stimulated. An experiment run is then started by pressing the button: infrared light results in an increase in the skin temperature of the rear paw. The experiment is terminated either by the experimental animal raising the rear paw (as an expression of the pain threshold being reached) or by automatic switching-off of the infrared light source when a prespecified maximum temperature has been reached. Light reflected by the paw is recorded as long as the experimental animal sits still. Withdrawal of the paw interrupts this reflection, after which the infrared light source is switched off and the time from switching on to switching off is recorded. The instrument is calibrated in such a way that the infrared light source increases the skin temperature to about 45 degrees Celsius in 10 s (Hargreaves et al. 1988). An instrument produced by Ugo Basile for this purpose is used for the testing.

CAR was purchased from Sigma-Aldrich. The specific cathepsin D inhibitors according to the invention were administered out intra-articularly 30 minutes before the CAR. Triamcinolone (TAC) in an amount of 10 μg/joint was used as positive control, and the solvent (vehicle) was used as negative control. The hyperalgesia is quoted as the difference in the withdrawal times between the inflamed and non-inflamed paw.

Result: TAC was capable of reducing the CAR-induced swelling, but the specific cathepsin D inhibitors according to the invention were not. In contrast, the specific cathepsin D inhibitors according to the invention were able to reduce the extent of thermal hyperalgesia as a function of the dose.

Assessment: it has been shown that the compounds of the present invention exert an anti-hyperalgesic action. This can be postulated, since the compounds exhibited no influence on inflammatory swelling and thus on the hyperalgesia trigger. It can thus be assumed that the compounds develop a pain-reducing action in humans.

EXAMPLE 8 Stability of the Compounds According to the Invention in Bovine Synovial Fluid

1.) Extraction of Bovine Synovial Fluid

In the preparation of bovine explants (for the diffusion chamber or other assays), either cow hoof (metacarpal joints) or cow knee is used. The synovial fluid can be obtained from both joints. To this end, the synovial fluid is carefully removed from the open joint using a 10 ml syringe and a cannula and transferred into prepared 2 ml Eppendorf vessels. The Eppendorf vessels are labelled depending on the animal (cow passport is available). It must be ensured here that blood does not enter the joint gap during preparation of the joints. If this is the case, the synovial fluid will become a reddish colour and must consequently be discarded. The synovial fluid is basically highly viscous and clear to yellowish in colour. The removal together with a macroscopic analysis of the synovial fluid is documented.

2.) Batch for Stability Testing of Substances in SF

In order to check the stability of individual compounds, a pool of four different bovine synovial fluids is mixed. To this end, about 1 ml per SF is used. The mixture is prepared directly in a 5 ml glass vessel. The SFs are mixed thoroughly, but carefully. No air bubbles or foam should form. To this end, a vortex unit is used at the lowest speed. The compounds to be tested are tested in an initial concentration (unless required otherwise) of 1 μM. After addition of the substance, the batch is again mixed thoroughly and carefully. For visual monitoring, all SF batches are photographed, and the pictures are filed in the eLabBio file for the corresponding experiment. FIG. 1 shows photo documentation of this type by way of example. The batches are incubated in the incubator for 48 h at 37° C. and 7.5% CO₂.

3.) Sampling

The sampling is carried out after the pre-agreed times (unless required otherwise, see below). 200 μl of the SF are removed from the mixture per time and transferred directly into a 0.5 ml “low-binding” Eppendorf vessel. “Low-binding” Eppendorf vessels are used in order to minimise interaction of the substances with the plastic of the vessels. 200 μl of acetonitrile have already been introduced into the Eppendorf vessel, so that a 1+1 mixture of the SF forms thereafter. This simplifies the subsequent analysis, but precipitation of protein may occur immediately after addition of the SF. This should be noted on the protocol. The 0 h sample is taken immediately after addition of the substance. This corresponds to the 100% value in the stability calculation. Ideally, the concentration employed should be retrieved here. The samples can be frozen at −20° C.

-   -   0 h     -   6 h     -   24 h     -   48 h

The negative control used is SF without substance. The positive control used is SF with 1 μM of substance. This corresponds to the 0 h value and thus 100% stability.

The samples are stored in “low-binding” Eppendorf vessels at −20° C. The samples are subsequently measured quantitatively.

4.) Data Processing

The concentrations measured (ng/ml) are plotted against the time in a graph (GraphPad Prism®). The percentage stability of the substance is determined here. The 100% value used is the initial value in the SF at time 0 h. The data are stored in eLabBio under the respective experiment number and reported in the MSR database (as percent stability after the corresponding incubation times).

5.) Results

All compounds measured remained stable.

EXAMPLE 9 In-Vitro Fluorescence Assay for Identification of Renin-Inhibitory Activity

In order to identify modulators of renin activity, a continuous enzymatic test was carried out with a synthetic peptide which carries a fluorescent group Edans (=(5-(aminoethyl)aminonaphthalenesulfonate) which is quenched by energy transfer from a Dabcyl (4′-dimethylaminoazobenzene-4-carboxylate) group on the same molecule, in Greiner 384-well microtitre plates. Cleavage of the peptidic substrate by renin causes an increase in the fluorescence intensity. In order to determine the efficacy of substances, the time-dependent increase in the fluorescence intensity in the presence of the substance was compared with the time-dependent increase in fluorescence in the absence of substances. The reference substance used was renin inhibitor 2 (Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His N-Boc-Lys methyl ester Z) (Sigma-Aldrich). The substrate used was renin FRET substrate I (DABCYL-g-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS) (Anaspec, Fremont Calif.). The enzyme employed was recombinant human renin (Proteos, Kalamazoo, Mich.) in a final concentration of 10 nM. The test was carried out in 50 mM Mops buffer, 1.5% (v/v) of DMSO, 0.1% (w/v) of Igepal®, pH 7.2, 0.5% (w/v) of BSA. 2 μl of each substance solution with serially diluted substance concentration were added to in each case 4 μl of renin solution and incubated at room temperature for 15 min. The reaction was started by addition of 4 μl of substrate solution (final concentration 5 μM). After carrying out a starting-point fluorescence measurement (excitation wavelength 340 nm/emission wavelength 495 nm) using an Envision multilabel reader (Perkin Elmer), the reaction was incubated at 37° C. for 60 min. The amount of peptide fragment cleaved off during the reaction time was subsequently measured by determination of the increase in the fluorescence intensity at 495 nm (excitation wavelength 340 nm).

Result: all compounds measured have an IC₅₀ of the renin selectivity of >30 μM.

EXAMPLE 10 Injection Vials

A solution of 100 g of a compound of the formula I and 5 g of disodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, filtered under sterile conditions, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of a compound of the formula I.

EXAMPLE 11 Solution

A solution is prepared from 1 g of a compound of the formula I, 9.38 g of NaH₂PO₄ 2H₂O, 28.48 g of Na₂HPO₄. 12 H₂O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 I and sterilised by irradiation. This solution can be used in the form of eye drops.

EXAMPLE 12 Ointment

500 mg of a compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

EXAMPLE 13 Ampoules

A solution of 1 kg of a compound of the formula I in 60 I of bidistilled water is filtered under sterile conditions, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of a compound of the formula I. 

The invention claimed is:
 1. A compound of formula I,

in which R¹ denotes a C₁₋₁₀-straight-chain or branched alkyl group, C₃₋₂₀-mono-, bi- or tricyclic cycloalkyl group, C₄₋₂₀-mono- or bicyclic cycloalkylalkyl group, C₃₋₂₀-mono- or bicyclic aryl group, C₄₋₂₀-mono- or bicyclic arylalkyl group, mono- or bicyclic heteroaryl group having 1-14 carbons and 1-7 heteroatoms from O, S or N, mono- or bicyclic heteroarylalkyl group having 2-20 C atoms and 1-7 heteroatoms selected independently of one another from O, S or N, which is unsubstituted or mono-, di- or trisubstituted by (—CH₂)_(n)OR⁷, ≡N, Hal, OCF₃, CF₃, ═O, A, (CH₂)_(n)CN, (CH₂)_(n)NR⁷SO₂R⁷, (CH₂)_(n)SO₂NR⁷R⁸, R² denotes C₁₋₁₀-a straight-chain or branched alkyl, cyclohexylethyl, benzyl or phenylethyl, each of which is unsubstituted or mono-, di- or trisubstituted by (CH₂)_(n)OR⁷ or Cl, R³ denotes a C₁₋₁₀-straight-chain or branched alkyl group, C₃₋₂₀-mono-, bi- or tricyclic cycloalkyl group, C₄₋₂₀-mono- or bicyclic cycloalkylalkyl group, mono- or bicyclic heterocycloalkyl group having 1-14 atoms and 1-7 heteroatoms selected independently of one another from O, S or N, mono- or bicyclic heterocycloalkylalkyl group having 2-20 C atoms and 1-7 heteroatoms selected independently of one another from O, S or N—C₃₋₂₀-mono- or bicyclic aryl group, C₄₋₂₀-mono- or bicyclic arylalkyl group, mono- or bicyclic heteroaryl group having 1-14 C atoms and 1-7 heteroatoms independently of one another selected from O, S or N, or mono- or bicyclic heteroarylalkyl group having 2-20 C atoms and 1-7 heteroatoms selected independently of one another from O, S or N, which is unsubstituted or mono-, di- or trisubstituted by (CH₂)_(n)OR⁷, ≡N, Hal, OCF₃, CF₃, (CH₂)_(n) COOR⁷, ═O, A, (CH₂)—CN, (CH₂)_(n)NR⁷SO₂R⁷, (CH₂)_(n)SO₂NR⁷R⁸, (CH₂)—N(C[Hal]₃)₂, (CH₂)_(n)CHOH(CH₂)_(n)OR⁷ or (CH₂)_(n)O(CH₂)_(m)OR⁷ R⁷, R⁸ are, independently of one another, H or A and, in NR⁷R⁸, R⁷ and R⁸, together with the N atom to which they are bonded, may form a 5-, 6- or 7-membered heterocycle, which may optionally contain one or two further heteroatoms selected from the group consisting of N, O and S, A is selected from the group consisting of alkyl, alkenyl, alkynyl and cycloalkyl, n, m are, independently of one another, 0, 1, 2, 3, 4, or 5, and Hal is, independently of one another, F, Cl, Br or I, or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios.
 2. A compound selected from the group consisting of:
 1. (R)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(3,4-dimethoxyphenyl)ethyl]propionamide,
 2. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methoxybenzyl)- 3-phenylpropionamide,
 3. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1- ethylpropyl)propionamide trifluoroacetate,
 4. (R)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide,
 5. (S)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)ethyl]-3-(4-methoxyphenyl)propionamide,
 6. (S)-3-(4-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- [2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide,
 7. (S)-3-(2,4-dichlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]propionamide,
 8. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxy- phenyl)ethyl]-3-phenylpropionamide,
 9. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)ethyl]propionamide,
 10. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-phenethyl-3- phenylpropionamide,
 11. (R)-N-[2-(4-chlorophenyl)ethyl]-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 12. (R)-N-[2-(2,4-dichlorophenyl)ethyl]-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 13. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide,
 14. (S)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)ethyl]-3-phenylpropionamide,
 15. (R)-N-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide,
 16. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- sulfamoylbenzyl)propionamide,
 17. (R)-N-(4-cyano-3-fluorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 18. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-(4-methoxyphenyl)propionamide,
 19. (R)-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide trifluoroacetate,
 20. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluorobenzyl)-3- phenylpropionamide,
 21. (R)-N-(3,4-difluorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 22. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide,
 23. (R)-N-(2-bromo-4,5-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide,
 24. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((1S,2R)-2- hydroxyindan-1-yl)-3-phenylpropionamide,
 25. (R)-3-cyclohexyl-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide,
 26. (R)-N-benzyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-methyl-3- phenylpropionamide,
 27. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-N-methyl-3-phenylpropionamide,
 28. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenylpropion- amide,
 29. (R)-N-(3,4-dichlorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 30. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-pyridin-4- ylmethylpropionamide,
 31. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-pyridin-2- ylmethylpropionamide,
 32. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-[3-(1H- tetrazol-5-yl)benzyl]propionamide,
 33. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isobutyl-3-phenyl- propionamide,
 34. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2,2-dimethyl- propyl)-3-phenylpropionamide,
 35. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methylbutyl)-3- phenylpropionamide,
 36. (R)-N-(4-tert-butylcyclohexyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 37. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methoxy- ethoxy)benzyl]-3-phenylpropionamide,
 38. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-hydroxy- ethoxy)benzyl]-3-phenylpropionamide,
 39. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-ethylpropyl)-3- phenylpropionamide,
 40. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-isopropyl-3-phenyl- propionamide,
 41. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-ethylbutyl)-3- phenylpropionamide,
 42. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-2-methyl- butyl)-3-phenylpropionamide,
 43. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)- 2-methylbutyl)propionamide,
 44. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-methoxybenzyl amide,
 45. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid isobutyl amide,
 46. (2R,3R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanecarboxylic acid 4-fluoro-3-methoxybenzyl amide,
 47. (R)-N-(2-benzo-1,3-dioxol-5-ylethyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide,
 48. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(2- pyridin-4-ylethyl)propionamide,
 49. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-hydroxypropionamide,
 50. (R)-3-tert-butoxy-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide,
 51. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-dimethoxybenzyl amide,
 52. (R)-N-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide,
 53. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide,
 54. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxybenzyl)- 3-phenylpropionamide,
 55. (R)-3-(2-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- [2-(3,4-dimethoxyphenyl)ethyl]propionamide,
 56. (R)-3-(4-chlorophenyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- [2-(3,4-dimethoxyphenyl)ethyl]propionamide,
 57. 5-((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)furan-2-carboxylic acid methyl ester,
 58. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-thiophen- 2-ylmethylpropionamide,
 59. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-ethoxypyridin-2- ylmethyl)-3-phenylpropionamide,
 60. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide,
 61. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-4-phenylbutyramide,
 62. (1S,3S,4S)-4-((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionylamino)-3-hydroxycyclohexanecarboxylic acid methyl ester,
 63. (R)-N-(3,5-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 64. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((R)-1-hydroxy- methyl-3-methylbutyl)-3-phenylpropionamide,
 65. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-((S)-1-hydroxy- methyl-3-methylbutyl)-3-phenylpropionamide,
 66. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-methyl- cyclohexyl)-3-phenylpropionamide,
 67. (2R,3R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-methyl- pentanoic acid isobutyl amide,
 68. R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid ((S)-2-methylbutyl) amide,
 69. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[1-(4- fluoro-3-methoxyphenyl)cyclopropyl]propionamide,
 70. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid [1-(4-fluoro-3-methoxyphenyl)cyclopropyl] amide,
 71. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[1-(4-fluoro-3- methoxyphenyl)cyclopropyl]-3-phenylpropionamide,
 72. (R)-3,N-dicyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- propionamide,
 73. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid cyclohexyl amide,
 74. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(tetra- hydropyran-4-yl)propionamide,
 75. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (tetrahydropyran-4-yl) amide,
 76. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1-methylpiperidin- 4-yl)-3-phenylpropionamide,
 77. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (1-methylpiperidin-4-yl) amide,
 78. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 79. (R)-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide,
 80. (R)-3-cyclohexyl-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide,
 81. (R)-3-cyclohexyl-2-{N′-[2-(3,5-dimethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide,
 82. (R)-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide,
 83. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)-1-(3-methoxy- phenyl)ethyl]-3-phenylpropionamide,
 84. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)-1-(3-methoxy- phenyl)ethyl]-3-phenylpropionamide,
 85. (S)-3-cyclohexyl-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide,
 86. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)- 1-(3-methoxyphenyl)ethyl]propionamide,
 87. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)- 1-(3-methoxyphenyl)ethyl]propionamide,
 88. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(tetra- hydropyran-4-ylmethyl)propionamide,
 89. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-methoxypropyl)- 3-phenylpropionamide,
 90. (S)-3-cyclohexyl-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide,
 91. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (tetrahydropyran-4-ylmethyl)propionamide,
 92. (S)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- methoxypropyl)propionamide,
 93. (R)-3-cyclohexyl-2-{N′-[3-(3,4-dimethoxyphenyl)propionyl]guanidino}-N- (4-fluoro-3-methoxybenzyl)propionamide,
 94. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N-(4- fluoro-3-methoxybenzyl)propionamide,
 95. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(4-methylpentanoyl)- guanidino]propionamide,
 96. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(indane-2-carbonyl)- guanidino]propionamide,
 97. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-dimethoxybenzyl amide,
 98. (R)-3-cyclohexyl-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3- methoxybenzyl)propionamide,
 99. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide,
 100. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-[N′-(3-phenylpropionyl)- guanidino]propionamide,
 101. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(3-phenylpropionyl)- guanidino]propionamide,
 102. (R)-3-cyclohexyl-N-((S)-2-methylbutyl)-2-(N′-phenylacetylguanidino)- propionamide,
 103. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-3-cyclohexyl-N- isobutylpropionamide,
 104. (R)-2-[N′-(2-benzo-1,3-dioxol-5-ylacetyl)guanidino]-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide,
 105. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-[N′-(3-phenylpropionyl)guanidino]- propionamide,
 106. (R)-3-cyclohexyl-2-[N′-(indane-2-carbonyl)guanidino]-N-isobutylpropion- amide,
 107. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(indane-2-carbonyl)guanidino]-3-phenyl- propionamide,
 108. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[3-(3,4-dimethoxyphenyl)propionyl]- guanidino}-3-phenylpropionamide,
 109. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-isobutylpropionamide,
 110. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-N-(3,4- dimethoxybenzyl)-3-phenylpropionamide,
 111. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid isobutyl amide,
 112. (R)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-methoxybenzyl amide,
 113. (R)-3-cyclohexyl-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-N-((S)-2- methylbutyl)propionamide,
 114. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-methoxy- phenyl)acetyl]guanidino}propionamide,
 115. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-(N′-phenylacetylguanidino)- propionamide,
 116. (R)-3-cyclohexyl-N-isobutyl-2-[N′-(4-methylpentanoyl)guanidino]propion- amide,
 117. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}- propionamide,
 118. (R)-3-cyclohexyl-2-[N′-(2-cyclohexylacetyl)guanidino]-N-isobutylpropion- amide,
 119. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(4-methylpentanoyl)guanidino]-3- phenylpropionamide,
 120. (R)-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(3,4-dimethoxybenzyl)-3- phenylpropionamide,
 121. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide,
 122. (R)-N-(3-methoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)acetyl]guanidino}-3- phenylpropionamide,
 123. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-methoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 124. (R)-2-[N′-(2-cyclohexylacetyl)guanidino]-N-(4-fluoro-3-methoxybenzyl)-3- phenylpropionamide,
 125. (R)-N-isobutyl-2-{N′-[2-(4-methoxyphenyl)acetyl]guanidino}-3-phenyl- propionamide,
 126. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(4-methoxyphenyl)acetyl]guanidino}- 3-phenylpropionamide,
 127. (R)-N-isobutyl-2-[N′-(2-phenoxyacetyl)guanidino]-3-phenylpropionamide,
 128. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(4-trifluoromethylphenyl)- acetyl]guanidino}propionamide,
 129. (R)-3-phenyl-N-(4-sulfamoylbenzyl)-2-{N′-[2-(4-trifluoromethoxyphenyl)- acetyl]guanidino}propionamide,
 130. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(4-trifluoromethoxyphenyl)- acetyl]guanidino}propionamide,
 131. (R)-N-isobutyl-2-[N′-(3-methylbutyryl)guanidino]-3-phenylpropionamide,
 132. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-[N′-(3-methylbutyryl)guanidino]-3- phenylpropionamide,
 133. (R)-2-[N′-(3-methylbutyryl)guanidino]-3-phenyl-N-(4-sulfamoylbenzyl)- propionamide,
 134. (R)-N-(3,4-dimethoxybenzyl)-2-[N′-(3-methylbutyryl)guanidino]-3-phenyl- propionamide,
 135. (R)-4-methyl-2-[N′-(3-methylbutyryl)guanidino]-pentanoic acid 3,4- dimethoxybenzyl amide,
 136. (R)-N-isobutyl-2-(N′-isobutyrylguanidino)-3-phenylpropionamide,
 137. (R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N′-isobutyrylguanidino)-3-phenyl- propionamide,
 138. (R)-2-(N′-isobutyrylguanidino)-3-phenyl-N-(4-sulfamoylbenzyl)propion- amide,
 139. (R)-N-(3,4-dimethoxybenzyl)-2-(N′-isobutyrylguanidino)-3-phenylpropion- amide,
 140. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(2-methyl- sulfamoylbenzyl)-3-phenylpropionamide,
 141. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 142. (R)-N-benzo-1,3-dioxol-5-ylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 143. (R)-N-(2,3-dimethoxybenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 144. (R)-N-(3-bromobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide,
 145. (R)-N-(3-chlorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3- phenylpropionamide,
 146. (R)-N-benzyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionamide,
 147. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-N-[2-(3,4-dimethoxy- phenyl)ethyl]-3-phenylpropionamide,
 148. (S)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]- 2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide,
 149. (S)-3-(4-chlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2- {N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide,
 150. (R)-3-(2,4-dichlorophenyl)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]- 2-{N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide,
 151. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-(4-methoxyphenyl)-2- {N′-[2-(3-phenoxyphenyl)acetyl]guanidino}propionamide,
 152. (R)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N′-[2-(3-phenoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide,
 153. (S)-N-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-2-{N′-[2-(3-phenoxy- phenyl)acetyl]guanidino}-3-phenylpropionamide,
 154. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 155. (R)-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide,
 156. (R)-3-cyclohexyl-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide,
 157. (R)-3-cyclohexyl-2-{N′-[2-(2,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide,
 158. (R)-2-[N′-(2-adamantan-1-ylacetyl)guanidino]-N-(3,4-dimethoxybenzyl)-3- phenylpropionamide,
 159. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-isobutylpropion- amide,
 160. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-3-cyclohexyl-N-(4-fluoro-3- methoxybenzyl)propionamide,
 161. 2-[N′-(2-adamantan-1-ylacetyl)guanidino]-N-(4-fluoro-3-methoxybenzyl)-3- phenylpropionamide,
 162. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- sulfamoylbenzyl)propionamide,
 163. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid cyclopropylmethyl amide,
 164. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-sulfamoylbenzyl amide,
 165. (R)-3-cyclohexyl-N-cyclopropylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide,
 166. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(S)- 1-(3-methoxyphenyl)ethyl]propionamide,
 167. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[(R)- 1-(3-methoxyphenyl)ethyl]propionamide,
 168. (R)-3-cyclohexyl-N-cyclohexylmethyl-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide,
 169. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (tetrahydropyran-4-ylmethyl)propionamide,
 170. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- methoxypropyl)propionamide,
 171. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (tetrahydrothiopyran-4-yl)propionamide,
 172. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(tetra- hydrothiopyran-4-yl)propionamide,
 173. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (tetrahydrothiopyran-4-yl) amide,
 174. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (tetrahydropyran-4-yl)propionamide,
 175. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(1- methylpiperidin-4-yl)propionamide,
 176. (R)-N-(5-chlorothiophen-2-ylmethyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide,
 177. (R)-N-(5-chlorothiophen-2-ylmethyl)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide,
 178. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3-fluoro-4-meth- oxybenzyl)-3-phenylpropionamide,
 179. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- fluoro-4-methoxybenzyl)propionamide,
 180. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3-fluoro-4-methoxybenzyl amide,
 181. (R)-3-cyclohexyl-N-(3,4-difluorobenzyl)-2-{N′-[2-(3,4-dimethoxyphenyl)- acetyl]guanidino}propionamide,
 182. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3,4-difluorobenzyl amide,
 183. (R)-N-(6-chloropyridin-3-ylmethyl)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide,
 184. (R)-N-((S)-sec-butyl)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide,
 185. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- (trans-4-hydroxycyclohexyl)propionamide,
 186. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (6-chloropyridin-3-ylmethyl) amide,
 187. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluorobenzyl)propionamide,
 188. (R)-3-cyclohexyl-N-cyclopropyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide,
 189. (R)-3-cyclohexyl-N-cyclopentyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide,
 190. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid 4-fluorobenzyl amide,
 191. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid cyclopentyl amide,
 192. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid ((S)-sec-butyl) amide,
 193. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid ((R)-sec-butyl) amide,
 194. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (trans-4-hydroxycyclohexyl) amide,
 195. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid (cis-4-hydroxycyclohexyl) amide,
 196. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (S)-indan-1-yl amide amide,
 197. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (R)-indan-1-ylamide amide,
 198. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (4-methoxyindan-2-yl) amide,
 199. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid (5-methoxyindan-2-yl) amide,
 200. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentane- carboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide,
 201. (R)-3-cyclohexyl-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide,
 202. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(cis- 4-hydroxycyclohexyl)propionamide,
 203. (R)-N-((R)-sec-butyl)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide,
 204. (R)-N-(3,4-dimethoxybenzyl)-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]- guanidino}-3-phenylpropionamide,
 205. (R)-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide,
 206. (R)-3-cyclohexyl-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide,
 207. (R)-3-cyclohexyl-2-{N′-[2-(2,5-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide,
 208. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(S)- indan-1-ylpropionamide)propionamide,
 209. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(R)- indan-1-ylpropionamide,
 210. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- methoxyindan-2-yl)propionamide,
 211. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(5- methoxyindan-2-yl)propionamide,
 212. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide,
 213. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3-methoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide,
 214. (R)-3-cyclohexyl-2-{N′-[2-(4-fluoro-3-methoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide,
 215. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3- methoxyphenyl)acetyl]guanidino}propionamide,
 216. (R)-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4-methoxyphenyl)- acetyl]guanidino}-3-phenylpropionamide,
 217. (R)-3-cyclohexyl-2-{N′-[2-(3-fluoro-4-methoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide,
 218. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide,
 219. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-[N′-(2-tetrahydropyran-4-yl- acetyl)guanidino]propionamide,
 220. (R)-3-cyclohexyl-N-isobutyl-2-[N′-(2-tetrahydropyran-4-ylacetyl)guanidino]- propionamide,
 221. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-tetrahydropyran-4- ylacetyl)guanidino]propionamide,
 222. (R)-3-cyclohexyl-2-{N′-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-(4-fluoro-3-methoxybenzyl)propionamide,
 223. (R)-3-cyclohexyl-2-{N′-[2-(2,6-difluoro-4-methoxyphenyl)acetyl]- guanidino}-N-isobutylpropionamide,
 224. (R)-3-cyclohexyl-2-[N′-(3, 3-dimethylbutyryl)guanidino]-N-(4-fluoro-3- methoxybenzyl)propionamide,
 225. (R)-3-cyclohexyl-2-[N′-(3,3-dimethylbutyryl)guanidino]-N-isobutylpropion- amide.
 226. (R)-3-cyclohexyl-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N- isobutylpropionamide,
 227. (R)-2-{N′-[2-(3,4-diethoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide,
 228. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide, (R)-2-{N′-[2-(2-bromo-4-methoxy- phenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutylpropionamide,
 229. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclohexyl-N- isobutylpropionamide,
 230. (R)-2-{N′-[2-(2-bromo-4-methoxyphenyl)acetyl]guanidino}-3-cyclohexyl-N- (4-fluoro-3-methoxybenzyl)propionamide,
 231. (S)-2-benzyl-4-{N′-[(R)-1-(4-fluoro-3-methoxybenzylcarbamoyl)-2- phenylethyl]guanidino}-4-oxobutyric acid methyl ester,
 232. (S)-2-benzyl-4-[N′-((R)-2-cyclohexyl-1-isobutylcarbamoylethyl)- guanidino]-4-oxobutyric acid methyl ester,
 233. (S)-2-benzyl-4-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid methyl ester,
 234. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide,
 235. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutyl- propionamide,
 236. (R)-2-{N′-[2-(2-bromophenyl)acetyl]guanidino}-N-(4-fluoro-3-methoxy- benzyl)-3-phenylpropionamide,
 237. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-((S)-5-oxo- pyrrolidin-2-yl)acetyl]guanidino}propionamide,
 238. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-((S)-5-oxopyrrolidin-2-yl)acetyl]- guanidino}propionamide,
 239. (S)-2-benzyl-4-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzyl- carbamoyl)ethyl]guanidino}-4-oxobutyric acid,
 240. (R)-N-(3,4-dimethoxybenzyl)-3-phenyl-2-{N′-[2-(2,3,4-trimethoxyphenyl)- acetyl]guanidino}propionamide,
 241. (R)-N-(4-fluoro-3-methoxybenzyl)-3-phenyl-2-{N′-[2-(2,3,4-trimethoxy- phenyl)acetyl]guanidino}propionamide,
 242. (R)-3-cyclohexyl-N-isobutyl-2-{N′-[2-(2,3,4-trimethoxyphenyl)acetyl]- guanidino}propionamide,
 243. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2,3,4- trimethoxyphenyl)acetyl]guanidino}propionamide,
 244. (R)-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(3,4-dimethoxy- benzyl)-3-phenylpropionamide,
 245. (R)-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide,
 246. (R)-3-cyclohexyl-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N- isobutylpropionamide,
 247. (R)-3-cyclohexyl-2-{N′-[2-(3,4-difluorophenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide,
 248. (R)-N-cyclobutyl-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]- guanidino}propionamide,
 249. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid cyclobutyl amide,
 250. (R)-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N-(4-fluoro-3- methoxybenzyl)-3-phenylpropionamide,
 251. (R)-3-cyclohexyl-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N- isobutylpropionamide,
 252. (R)-3-cyclohexyl-2-{N′-[2-(1-ethylpiperidin-4-yl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide,
 253. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- trifluoromethylbenzyl)propionamide,
 254. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-trifluoromethylbenzyl amide,
 255. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-trifluoromethylbenzyl)propionamide,
 256. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-trifluoromethylbenzyl amide,
 257. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- trifluoromethoxybenzyl)propionamide,
 258. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3-trifluoromethoxybenzyl amide,
 259. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N′-[2-(4- fluoro-3-trifluoromethylphenyl)acetyl]guanidino}propionamide,
 260. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N′-[2-(4-fluoro- 3-trifluoromethylphenyl)acetyl]guanidino}propionamide,
 261. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2,4,6-trifluoro- phenyl)acetyl]guanidino}propionamide,
 262. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethoxybenzyl)-2-{N′-[2-(2,4,6- trifluorophenyl)acetyl]guanidino}propionamide,
 263. (R)-3-cyclohexyl-N-(4-fluoro-3-trifluoromethylbenzyl)-2-{N′-[2-(2,4,6- trifluorophenyl)acetyl]guanidino}propionamide,
 264. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-fluoro-3- trifluoromethylphenyl)acetyl]guanidino}propionamide,
 265. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- fluoro-3-trifluoromethoxybenzyl)propionamide,
 266. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-fluoro-3-trifluoromethoxybenzyl amide,
 267. (R)-N-[(S)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2-{N′- [2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide,
 268. (R)-N-[(R)-1-(3-chlorophenyl)-2-oxopyrrolidin-3-yl]-3-cyclohexyl-2-{N′- [2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide,
 269. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanecarboxylic acid 3-(1H-tetrazol-5-yl)benzyl amide,
 270. (R)-2-{N′-[2-(2-bromo-4,5-dimethoxyphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide,
 271. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-fluoro-4- trifluoromethoxyphenyl)acetyl]guanidino}propionamide,
 272. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4- (1H-tetrazol-5-yl)benzyl]propionamide,
 273. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 4-(1H-tetrazol-5-yl)benzyl amide,
 274. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-isobutyl- propionamide,
 275. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide,
 276. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- fluoro-4-(1H-tetrazol-5-yl)benzyl]propionamide,
 277. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-fluoro-4-(1H-tetrazol-5-yl)benzyl amide,
 278. (R)-2-{N′-[2-(2-bromo-4-trifluoromethylphenyl)acetyl]guanidino}-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide,
 279. (R)-2-[N′-((2S,4R)-1-acetyl-4-methoxypyrrolidine-2-carbonyl)guanidino]- 3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)propionamide,
 280. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-piperidin-1-yl- acetyl)guanidino]propionamide,
 281. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- sulfamoylbenzyl)propionamide,
 282. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-morpholin-4-yl- acetyl)guanidino]propionamide,
 283. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-sulfamoyl- phenyl)acetyl]guanidino}propionamide,
 284. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(2-fluoro-4- methoxyphenyl)acetyl]guanidino}propionamide,
 285. (R)-3-cyclohexyl-2-{N′-[2-(2-fluoro-4-methoxyphenyl)acetyl]guanidino}- N-isobutylpropionamide,
 286. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl]acetyl}guanidino)propionamide,
 287. (R)-2-{N′-[2-(3-cyanophenyl)acetyl]guanidino}-3-cyclohexyl-N-(4-fluoro- 3-methoxybenzyl)propionamide,
 288. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(3-methane- sulfonylaminophenyl)acetyl]guanidino}propionamide,
 289. 4-[((R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- propionylamino)methyl]benzoic acid methyl ester,
 290. 4-[((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester,
 291. 4-[((R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl- propionylamino)methyl]benzoic acid methyl ester,
 292. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propionamide,
 293. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl amide,
 294. 4-(2-{N′-[(R)-2-cyclohexyl-1-(4-fluoro-3-methoxybenzylcarbamoyl)ethyl]- guanidino}-2-oxoethyl)-2-ethoxybenzoic acid ethyl ester,
 295. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-pyridin-2-yl- acetyl)guanidino]propionamide,
 296. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-[N′-(2-isobutoxy- acetyl)guanidino]propionamide,
 297. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 4-(1,2,3-thiadiazol-4-yl)benzyl amide,
 298. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-(3- sulfamoylbenzyl)propionamide,
 299. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(4- (1,2,3-thiadiazol-4-yl)benzyl)propionamide,
 300. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5-methyl- 1,2,4-oxadiazol-3-yl)benzyl]-3-phenylpropionamide,
 301. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-tetrazol-1-yl- phenyl)acetyl]guanidino}propionamide,
 302. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl- imidazol-1-yl)benzyl]-3-phenylpropionamide,
 303. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (2-methylimidazol-1-yl)benzyl]propionamide,
 304. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 3-(2-methylimidazol-1-yl)benzyl amide,
 305. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- (1,2,4-triazol-1-yl)benzyl)propionamide,
 306. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- 1,2,4-triazol-1-ylbenzyl)propionamide,
 307. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(1,2,4-triazol-1-yl)benzyl amide,
 308. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentane- carboxylic acid 4-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide,
 309. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-(5-hydroxy- 1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide,
 310. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4- (5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide,
 311. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide,
 312. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide,
 313. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(5-hydroxy- 1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide,
 314. (R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl-N-[4-(1H- tetrazol-5-yl)benzyl]propionamide,
 315. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(4- 1,2,3-thiadiazol-4-ylbenzyl)propionamide,
 316. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (2-methyl-2H-pyrazol-3-yl)benzyl]propionamide,
 317. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(2-methyl-2H-pyrazol-3-yl)benzyl amide,
 318. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(2-methyl-2H- pyrazol-3-yl)benzyl]-3-phenylpropionamide,
 319. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3- (1-methyl-1H-pyrazol-3-yl)benzyl]propionamide,
 320. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-(1-methyl-1H-pyrazol-3-yl)benzyl amide,
 321. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[3-(1-methyl-1H- pyrazol-3-yl)benzyl]-3-phenylpropionamide,
 322. (R)-2-{N′-[2-(4-chloro-2-fluorophenyl)acetyl]guanidino}-3-cyclohexyl-N- (4-fluoro-3-methoxybenzyl)propionamide,
 323. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-(3- thiazol-2-ylbenzyl)propionamide,
 324. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 3-thiazol-2-ylbenzyl amide,
 325. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-3-phenyl-N-(3- thiazol-2-ylbenzyl)propionamide,
 326. (R)-2-[N′-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3-cyclo- hexyl-N-(4-fluoro-3-methoxybenzyl)propionamide,
 327. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N-(4- fluoro-3-methoxybenzyl)propionamide,
 328. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4- fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl]propionamide,
 329. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 4-fluoro-3-(5-hydroxy-1,3,4-oxadiazol-2-yl)benzyl amide,
 330. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3-(5- hydroxy-1,3,4-oxadiazol-2-yl)benzyl]-3-phenylpropionamide,
 331. (R)-2-[N′-((1S,4R)-2-bicyclo[2.2.1]hept-2-ylacetyl)guanidino]-3-cyclo- hexyl-N-[3-(1H-tetrazol-5-yl)benzyl]propionamide,
 332. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide,
 333. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[4-(2H-tetrazol- 5-yl)phenyl]acetyl}guanidino)propionamide,
 334. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-{N′-[2-(4-propylcyclo- hexyl)acetyl]guanidino}propionamide,
 335. (R)-3-cyclohexyl-2-{N′-[2-(4-propylcyclohexyl)acetyl]guanidino}-N-[3- (1H-tetrazol-5-yl)benzyl]propionamide,
 336. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4-fluoro-3-(2H- tetrazol-5-yl)benzyl]-3-phenylpropionamide,
 337. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N-[4- fluoro-3-(2H-tetrazol-5-yl)benzyl]propionamide,
 338. (R)-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-4-methylpentanoic acid 4-fluoro-3-(2H-tetrazol-5-yl)benzyl amide,
 339. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- {(S)-1-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide,
 340. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethylphenyl)acetyl]guanidino}-N-{(S)- l-[3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide,
 341. (R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}-N- {(S)-1-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]ethyl}propionamide,
 342. (R)-N-[4-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide,
 343. 4-[((R)-3-cyclohexyl-2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}- propionylamino)methyl]benzoic acid,
 344. 3-[((R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-3-cyclohexyl- propionylamino)methyl]benzoic acid methyl ester,
 345. 3-[((R)-2-{N′-[2-(4-chlorophenyl)acetyl]guanidino}-4-methyl- pentanoylamino)methyl]benzoic acid methyl ester,
 346. (R)-N-[3-(bistrifluoromethylamino)benzyl]-3-cyclohexyl-2-{N′-[2-(3,4- dimethoxyphenyl)acetyl]guanidino}propionamide,
 347. (R)-3-cyclohexyl-N-(4-fluoro-3-methoxybenzyl)-2-(N′-{2-[3-(2H-tetrazol- 5-yl)phenyl]acetyl}guanidino)propionamide,
 348. (R)-N-{1-[4-(bistrifluoromethylamino)phenyl]cyclopropyl}-3-cyclohexyl- 2-{N′-[2-(3,4-dimethoxyphenyl)acetyl]guanidino}propionamide,
 349. (R)-3-cyclohexyl-N-((R)-2,3-dihydroxypropyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide,
 350. (R)-3-cyclohexyl-N-((S)-2,3-dihydroxypropyl)-2-{N′-[2-(3,4-dimethoxy- phenyl)acetyl]guanidino}propionamide,

or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios.
 3. A process for the preparation of the compounds of the formula I according to claim 1, a) obtaining a compound of the formula VII,

in which R¹ is as defined in claim 1, by acylation of a pyrazole-1-carboxamidine of the formula XI

using an acid of the formula X or an acid derivative of the formula Xa,

in which R¹ has the meanings indicated above and X denotes a halogen, alkyl- or aryloxycarbonyloxy, and obtaining a compound of the formula VIII

in which R¹ has the meanings indicated above and R¹¹ denotes a protecting group for amines or imines, by reacting a guanidine of the formula IX,

in which R¹¹ has the meanings indicated above, with an acid of the formula X or an activated acid derivative of the formula Xa,

in which R¹ and X have the meanings indicated above, and preparing a compound of the formula III,

in which R¹ and R¹¹ have the meanings indicated above and L a leaving group selected from a 1-pyrrazolyl group and a trifluoromethylsulfonylamino group, by either in the case where L denotes a 1-pyrazolyl group, introducing a protecting group R¹¹ into a compound of the formula VII, or, in the case where L denotes a trifluoromethylsulfonylamino group, preparing a compound of the formula III by reaction of a compound of the formula VIII with trifluoromethanesulfonic anhydride, and preparing a compound of the formula II,

in which R² and R³ are as defined in claim 1, by preparing a compound of the formula IV,

in which R², R³ and R¹¹ have the meanings indicated above, by coupling an amino acid of the formula V,

in which R³ and R¹¹ have the meanings indicated above, to an amine of the formula VI, H₂N—R³  VI in which R³ has the meanings indicated above, and preparing a compound of the formula II by removing R¹¹ from a compound of the formula IV, and then obtaining a compound of the formula Ia

in which R¹, R², R³ and R¹¹ have the meanings indicated above, by reaction of an amine of the formula II with an acylguanidine of the formula III, and a compound of the formula I is obtained by removing R¹¹ from a compound of the formula Ia, or b) reacting a compound of the formula VII with an amine of the formula II, or c) converting the base of a compound of the formula I into one of its salts by treatment with an acid, or d) converting an acid of a compound of the formula I into one of its salts by treatment with a base.
 4. A method for inhibiting cathepsin D, comprising administering to a subject in need thereof an effective amount of a Compound according to claim 1 or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios.
 5. A pharmaceutical composition comprising at least one compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios, and a pharmaceutically acceptable carrier.
 6. A pharmaceutical composition according to claim 5, comprising further excipients and/or adjuvants.
 7. A pharmaceutical composition comprising at least one compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active compound.
 8. A process for the preparation of a pharmaceutical composition comprising bringing a compound according to claim 1 and/or one of its physiologically acceptable salts, solvates, prodrugs or stereoisomers, including mixtures thereof in all ratios, into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant.
 9. A method for the treatment of physiological and/or pathophysiological states, selected from the group consisting of arthrosis, traumatic cartilage injuries, arthritis, pain, allodynia and hyperalgesia, comprising administering to a subject in need thereof an effective amount of a compound of claim
 1. 10. A method for the treatment of physiological and/or pathophysiological states selected from the group consisting of Alzheimer's disease, Huntington's disease, mucolipidosis, breast cancer, contact dermatitis, late-onset hypersensitivity reaction, inflammation, endometriosis, scarring, benign prostate hyperplasia, osteosarcoma, rickets, skin diseases, such as, for example, psoriasis, immunological diseases, autoimmune diseases and immunodeficiency diseases, comprising administering to a subject in need thereof an effective amount of a compound of claim
 1. 11. A method according to claim 9, wherein the administration is intra-articular administration.
 12. A set (kit) consisting of separate packs of a) an effective amount of a compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and b) an effective amount of a further medicament active compound. 